Curcumin, a component of a spice native to India, was first isolated in 1815 by Vogel and Pelletier from the rhizomes of Curcuma longa (turmeric) and, subsequently, the chemical structure of curcumin as diferuloylmethane was reported by Milobedzka et al. [(1910) 43., 2163-2170]. Since then, this polyphenol has been shown to exhibit antioxidant, anti-inflammatory, anticancer, antiviral, antibacterial, and antifungal activities. The current review primarily focuses on the anticancer potential of curcumin through the modulation of multiple cell signaling pathways. Curcumin modulates diverse transcription factors, inflammatory cytokines, enzymes, kinases, growth factors, receptors, and various other proteins with an affinity ranging from the pM to the mM range. Furthermore, curcumin effectively regulates tumor cell growth via modulation of numerous cell signaling pathways and potentiates the effect of chemotherapeutic agents and radiation against cancer. Curcumin can interact with most of the targets that are modulated by FDA-approved drugs for cancer therapy. The focus of this review is to discuss the molecular basis for the anticancer activities of curcumin based on preclinical and clinical findings.

Introduction

Carcinogenesis is a multistage process that stems from the perturbations of multiple cell signaling pathways [1,2]. Recent studies imply that in any cancer type, 300–500 normal genes are perturbed in one way or another, ultimately leading to the cancerous phenotype. Despite the fact that the cancers are characterized by the dysregulation of multiple signaling pathways, currently available cancer chemotherapeutics are mostly based on the modulation of a single target (Table 1) [3,4]. Mono-targeted drugs are found to be ineffective in most cases. Moreover, these drugs are often highly expensive and are beyond the reach of the vast majority of the world’s population. Notably, these drugs are linked with adverse side effects, which significantly limit their efficacy [5,6]. Thus, agents that are safe, relatively less expensive, multitargeted, and highly efficacious are demanded for the prevention and treatment of cancer [2]. Curcumin is one such compound that is safe, cost-effective, and has been found to exhibit cancer chemopreventive and therapeutic effects through multiple mechanisms, as shown by several preclinical and clinical studies [7,8,9,10]. This compound- derived from the rhizomes of the dietary spice, Curcuma longa, commonly known as turmeric and extensively used in Asian kitchens and for various medicinal purposes- was first discovered by two scientists from Harvard College Laboratory, Vogel and Pelletier, approximately two centuries ago [10,11]. Subsequently, the chemical structure of curcumin was reported as diferuloylmethane or 1,6-heptadiene-3,5-dione-1,7-bis(4-hydroxy-3-methoxyphenyl)-(1E,6E) by Milobedzka and colleagues [12]. Interestingly, this polyphenol has been shown to modulate the targets that are also inhibited by FDA-approved chemotherapeutic agents (Figure 1). However, its application as a therapeutic agent is obstructed to a certain degree owing to its color, lack of water solubility, and limited bioavailability [13]. To overcome these limitations, several approaches are being investigated in trials such as developing oral delivery methods for curcumin, including liposomes, polymeric micelles, nanoparticles, phospholipid complexes, and microemulsions [14].

Curcumin can modulate the targets that are inhibited by FDA-approved drugs for the treatment of cancer

Figure 1
Curcumin can modulate the targets that are inhibited by FDA-approved drugs for the treatment of cancer

Abbreviations: IKZF, Ikaros family zinc finger protein; ROS1: ROS Proto-Oncogene 1.

Figure 1
Curcumin can modulate the targets that are inhibited by FDA-approved drugs for the treatment of cancer

Abbreviations: IKZF, Ikaros family zinc finger protein; ROS1: ROS Proto-Oncogene 1.

Table 1
FDA-approved drugs for the treatment of cancer
DrugTargetCancer type
Alectinib Anaplastic lymphoma kinase ALK+, metastatic NSCLC 
Ceritinib Anaplastic lymphoma kinase ALK+, metastatic NSCLC 
Crizotinib ALK, c-ros oncogene 1 Metastatic ALK+, NSCLC 
Letrozole Aromatase Locally advanced or metastatic breast cancer 
Venetoclax BCL-2 CLL with 17p deletion 
Bosutinib BCR-ABL Ph+ chronic myelogenous leukemia 
Ponatinib BCR-ABL CML and Ph+ ALL 
Nilotinib HCl BCR-ABL CML 
Dasatinib BCR-ABL, SRC family Imatinib-resistant CML 
Imatinibmesylate BCR-ABL, PDGF, c-kit CML, GI stromal tumors 
Blinatumomab CD-19 Ph-relapsed /refractory B-cell precursor ALL 
Bexxar, Corixa CD-20 Follicular NHL after chemotherapy relapse 
Obinutuzumab CD-20 FL, relapsed after or are refractory to rituximab, CLL 
Rituximab CD-20 NHL 
Ibritumomabtiuxetan CD-20 NHL 
Ofatumumab CD-20 Recurrent/progressive CLL 
Brentuximabvedotin CD-30 HL at high risk of relapse, pancreatic NET 
Gemtuzumabozogamicin CD-33 CD33 positive acute myeloid leukemia 
Daratumumab CD-38 Multiple myeloma with prior therapy 
Campath CD-52 B-cell CLL 
Ipilimumab CTLA-4 Metastatic melanoma 
Cetuximab EGF receptor EGFR-expressing, metastatic CRC 
Erlotinib Human EGFR 1 Advanced refractory metastatic NSCLC 
Gefitinib EGFR Second- line treatment of NSCLC 
Osimertinib EGFR Metastatic NSCLC 
Necitumumab EGFR Metastatic squamous NSCLC 
Panitumumab EGFR CRC 
Ado-trastuzumab-EM HER 2 HER2+ metastatic breast cancer 
Afatinib HER2 receptor 2 Metastatic NSCLC with EGFR mutations 
Trastuzumab HER2 Gastric cancer 
Pertuzumab HER2 HER2+ metastatic breast cancer 
Herceptin HER 2 Metastatic breast cancer 
Lapatinib HER 2 Breast cancer 
Panobinostat HDAC Multiple myeloma 
Romidepsin HDAC CTCL 
Belinostat Hh pathway Relapsed or refractory PTCL 
Odomzo Hh pathway Locally advanced BCC 
Sonidegib Hh pathway Locally advanced BCC 
Lenalidomide TNF, NF-κB, proteasome Mantle cell lymphoma 
Aldesleukin IL-2 Metastatic melanoma 
Pomalidomide IL-2, 6, and 10; IFNγ Relapsed and refractory multiple myeloma 
Siltuximab IL-6 MCD in patients who are HIV− and HHV8− 
Ibrutinib Bruton’s tyrosine kinase Mantle cell lymphoma, CLL Waldenstrom’s macroglobulinemia 
Palbociclib CDK 4 and 6 ER+, HER2− breast cancer 
Ruxolitinib Janus kinase 1 and 2 Polycythemia vera 
Cobimetinib Mitogen-activated protein kinase BRAF V600E /V600K metastatic melanoma 
Trametinib MAPK Unresectable or metastatic melanoma 
Trametinib + Dabrafenib MAPK, v-Raf Unresectable or metastatic melanoma 
Idelalisib Phosphoinositide 3- kinase Relapsed CLL, follicular B-cell NHL, SLL 
Vemurafenib v-Raf Melanoma 
Dabrafenib v-Raf Metastatic melanoma 
Everolimus mTOR Advanced pancreatic NET, GI/lung NET, recurrent CLLs, Hormone receptor+, HER2- breast cancer 
Temsirolimus mTOR RCC 
Olaparib PARP Advanced ovarian cancer 
Nivolumab PD-1 RCC, metastatic melanoma, and NSCLC 
Pembrolizumab PD-1 NSCLC, metastatic melanoma 
Bortezomib Proteasome Multiple myeloma with prior therapies 
Carfilzomib Proteasome Multiple myeloma 
Ixazomib Proteasome Multiple myeloma with prior therapy 
Denosumab RANKL Giant cell tumor of bone 
Clofarabine TS ALL in pediatric patients 
Axitinib VEGF 1,2,3, c-kit, PDGF Advanced RC 
Bevacizumab VEGF Metastatic carcinoma of colon, cervix, renal 
Ziv-aflibercept VEGF Metastatic CRC 
Cabozantinib VEGFR-2, c-Met Metastatic medullary thyroid cancer, RCC 
Lenvatinib VEGFR 1, 2, and 3 Thyroid cancer 
Pazopanib VEGFR, c-kit, FGFR, PDGFR RCC, soft tissue sarcoma 
Sorafenib VEGFR, PDGFR, Raf RCC, thyroid carcinoma 
Sunitinib malate VEGFR, PDGFR, c-kit Pancreatic NET 
Ramucirumab VEGFR 2 Gastric cancer, Metastatic NSCLC, and CRC 
Vandetanib VEGFR, EGFR, RET, Thyroid cancer 
Regorafenib VEGFR2-TIE2 GI stromal tumor, CRC 
DrugTargetCancer type
Alectinib Anaplastic lymphoma kinase ALK+, metastatic NSCLC 
Ceritinib Anaplastic lymphoma kinase ALK+, metastatic NSCLC 
Crizotinib ALK, c-ros oncogene 1 Metastatic ALK+, NSCLC 
Letrozole Aromatase Locally advanced or metastatic breast cancer 
Venetoclax BCL-2 CLL with 17p deletion 
Bosutinib BCR-ABL Ph+ chronic myelogenous leukemia 
Ponatinib BCR-ABL CML and Ph+ ALL 
Nilotinib HCl BCR-ABL CML 
Dasatinib BCR-ABL, SRC family Imatinib-resistant CML 
Imatinibmesylate BCR-ABL, PDGF, c-kit CML, GI stromal tumors 
Blinatumomab CD-19 Ph-relapsed /refractory B-cell precursor ALL 
Bexxar, Corixa CD-20 Follicular NHL after chemotherapy relapse 
Obinutuzumab CD-20 FL, relapsed after or are refractory to rituximab, CLL 
Rituximab CD-20 NHL 
Ibritumomabtiuxetan CD-20 NHL 
Ofatumumab CD-20 Recurrent/progressive CLL 
Brentuximabvedotin CD-30 HL at high risk of relapse, pancreatic NET 
Gemtuzumabozogamicin CD-33 CD33 positive acute myeloid leukemia 
Daratumumab CD-38 Multiple myeloma with prior therapy 
Campath CD-52 B-cell CLL 
Ipilimumab CTLA-4 Metastatic melanoma 
Cetuximab EGF receptor EGFR-expressing, metastatic CRC 
Erlotinib Human EGFR 1 Advanced refractory metastatic NSCLC 
Gefitinib EGFR Second- line treatment of NSCLC 
Osimertinib EGFR Metastatic NSCLC 
Necitumumab EGFR Metastatic squamous NSCLC 
Panitumumab EGFR CRC 
Ado-trastuzumab-EM HER 2 HER2+ metastatic breast cancer 
Afatinib HER2 receptor 2 Metastatic NSCLC with EGFR mutations 
Trastuzumab HER2 Gastric cancer 
Pertuzumab HER2 HER2+ metastatic breast cancer 
Herceptin HER 2 Metastatic breast cancer 
Lapatinib HER 2 Breast cancer 
Panobinostat HDAC Multiple myeloma 
Romidepsin HDAC CTCL 
Belinostat Hh pathway Relapsed or refractory PTCL 
Odomzo Hh pathway Locally advanced BCC 
Sonidegib Hh pathway Locally advanced BCC 
Lenalidomide TNF, NF-κB, proteasome Mantle cell lymphoma 
Aldesleukin IL-2 Metastatic melanoma 
Pomalidomide IL-2, 6, and 10; IFNγ Relapsed and refractory multiple myeloma 
Siltuximab IL-6 MCD in patients who are HIV− and HHV8− 
Ibrutinib Bruton’s tyrosine kinase Mantle cell lymphoma, CLL Waldenstrom’s macroglobulinemia 
Palbociclib CDK 4 and 6 ER+, HER2− breast cancer 
Ruxolitinib Janus kinase 1 and 2 Polycythemia vera 
Cobimetinib Mitogen-activated protein kinase BRAF V600E /V600K metastatic melanoma 
Trametinib MAPK Unresectable or metastatic melanoma 
Trametinib + Dabrafenib MAPK, v-Raf Unresectable or metastatic melanoma 
Idelalisib Phosphoinositide 3- kinase Relapsed CLL, follicular B-cell NHL, SLL 
Vemurafenib v-Raf Melanoma 
Dabrafenib v-Raf Metastatic melanoma 
Everolimus mTOR Advanced pancreatic NET, GI/lung NET, recurrent CLLs, Hormone receptor+, HER2- breast cancer 
Temsirolimus mTOR RCC 
Olaparib PARP Advanced ovarian cancer 
Nivolumab PD-1 RCC, metastatic melanoma, and NSCLC 
Pembrolizumab PD-1 NSCLC, metastatic melanoma 
Bortezomib Proteasome Multiple myeloma with prior therapies 
Carfilzomib Proteasome Multiple myeloma 
Ixazomib Proteasome Multiple myeloma with prior therapy 
Denosumab RANKL Giant cell tumor of bone 
Clofarabine TS ALL in pediatric patients 
Axitinib VEGF 1,2,3, c-kit, PDGF Advanced RC 
Bevacizumab VEGF Metastatic carcinoma of colon, cervix, renal 
Ziv-aflibercept VEGF Metastatic CRC 
Cabozantinib VEGFR-2, c-Met Metastatic medullary thyroid cancer, RCC 
Lenvatinib VEGFR 1, 2, and 3 Thyroid cancer 
Pazopanib VEGFR, c-kit, FGFR, PDGFR RCC, soft tissue sarcoma 
Sorafenib VEGFR, PDGFR, Raf RCC, thyroid carcinoma 
Sunitinib malate VEGFR, PDGFR, c-kit Pancreatic NET 
Ramucirumab VEGFR 2 Gastric cancer, Metastatic NSCLC, and CRC 
Vandetanib VEGFR, EGFR, RET, Thyroid cancer 
Regorafenib VEGFR2-TIE2 GI stromal tumor, CRC 

Source: www.fda.gov [4].

Abbreviations: ALL, acute lymphoblastic leukemia; APL, acute promyelocytic leukemia; BCC, basal cell carcinoma; BCL-2, B-cell lymphoma-2; BCR-ABL, breakpoint cluster region-Abelson murine leukemia viral oncogene; CD, cluster of differentiation; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CTCL, cutaneous T-cell lymphoma; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; EGFR, epidermal growth factor receptor; FL, follicular lymphoma; GI, gastrointestinal; HDAC, histone deacetylase; HER-2, human epidermal growth factor receptor-2; Hh, hedgehog; IFNγ, interferon-γ; IL, interleukin; MCD, multicentric Castleman’s disease; NET, neuroendocrine tumors; NF-κB, nuclear factor κB; NSCLC, non-small cell lung cancer; PARP, poly ADP ribose polymerase; PD, programmed cell death protein; PDGF, platelet-derived growth factor; PTCL, peripheral T-cell lymphoma; RANKL, receptor activator of nuclear factor κB ligand; RCC, renal cell carcinoma; SCLC, small cell lung cancer; SLL, small lymphocytic lymphoma; TNF, tumor necrosis factor; TS, thymidylate synthase; VEGF, vascular endothelial growth factor; VOD, veno-occlusive disease.

The first clinical trial to examine the potential of curcumin against cancer was performed by Kuttan and colleagues in 1987; 62 patients with external cancerous lesions were enrolled [15]. In this study, treatment of the patients with an extract of turmeric and an ointment of curcumin was shown to reduce symptoms, together with decreased itching and smell. In 70% of the patients, dry lesions were noted and, in some cases, decreased lesion size as well as pain was observed [15]. This trial was succeeded by numerous clinical studies, many of which have now been completed successfully (Tables 2 and 3) [1537]. The efficacy of curcumin in colorectal cancer patients has been extensively studied by many groups. In a Phase IIa clinical trial consisting of patients with colorectal neoplasia, systemic delivery of curcumin conjugates (4 g/day for 30 days) decreased the number of aberrant crypt foci (ACF) by 40% [26]. The oral administration of curcumin has also been shown to improve the general health of colorectal cancer patients through enhanced p53 expression in tumor cells, leading to tumor cell apoptosis [25]. In another study, Garcea and colleagues showed that oral administration of curcumin (3.6 g/day for 7 days) aided the achievement of pharmacologically effective levels in the colorectum with insignificant dispersal outside the gut, and reduced M(1)G levels in malignant colorectal tissues [24]. Another study was undertaken to test curcumin acceptability in patients from colonic mucosa after oral administration and topical application [27]. In this trial, curcumin was found in high levels in the mucosa until 40 h after administration and was shown to be extremely safe [27]. As a single agent, curcumin was also used as standardized formulation of Curcuma extract in two other trials. The administration of this extract in advanced colorectal cancer patients demonstrated dose-dependent inhibition of basal and lipopolysaccharide (LPS)-induced prostaglandin E(2) production and was found to be safe and well tolerated [21,22]. The effect of curcumin alone and in combination with chemotherapeutic agents/radiation therapy was also studied in pancreatic cancer patients. In a Phase I/II clinical trial conducted by our group, oral administration of curcumin was well tolerated and inhibited the progression of cancer by down-regulating nuclear factor κB (NF-κB), cyclooxygenase-2 (COX-2), and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) in peripheral blood mononuclear cells (PBMCs) in advanced pancreatic cancer patients [29]. Studies were also conducted to investigate the efficacy and feasibility of gemcitabine and curcumin co-treatment in advanced pancreatic cancer patients. These studies recommended it to be safe, feasible, and might engender reduced oral curcumin dosage in order to attain systemic effect [30,31]. Additionally, it has been shown that repetitive systemic exposure to high concentrations of curcumin attained via Theracurmin® did not aggravate the adverse reactions in cancer patients receiving gemcitabine-based chemotherapy [32]. Curcumin has also been shown to be very effective in prostate cancer patients. Hejazi and colleagues investigated the effect of curcumin supplementation on the oxidative status of patients with prostate cancer undergoing radiotherapy and found a marked increase in total antioxidant capacity (TAC) and a decrease in SOD levels compared with the placebo group [34]. In another study, Ledda and colleagues evaluated the potential of Meriva®, a lecithinized curcumin, against benign prostatic hyperplasia (BPH). A remarkable decrease in urinary infection and urinary block as well as improved quality of life was observed in the Meriva®-treated hyperplasia patients compared with the untreated group [16]. In addition, co-treatment of curcumin with soy isoflavones was shown to suppress prostate-specific antigen (PSA) production in prostate cells via antiandrogen activity [33]. Besides this, curcumin has also been shown in many clinical trials to be very effective against different cancers [20,27,35,36].

Table 2
Completed clinical trials of curcumin in different cancers
CancerDose of curcuminPatientsClinical outcomeReference
BPH 1 g/d; 24 w 61 Reduced signs and symptoms of disease [16
Breast cancer 6 g/d; 7 d 14 Safe and well tolerated [17
Cancerous lesions Ointment 62 Reduced lesion size and pain [15
 0.5–1.2 g/d; 3 m 25 Well tolerated and efficacious [18
Cervical cancer 500 mg/d; 30 d 280 Enhanced HPV clearance rate [19
CML 3 × 5 g; 6 w 50 Decreased nitric oxide levels [20
Colorectal cancer P54FP/d; 29 d 15 Inhibited basal and LPS-induced PGE2 [21
 2.2 g/d; 4 m 15 Well tolerated [22
 0.45 and 3.6 g/d; 4 m 15 Well tolerated and efficacious [23
 0.45, 1.8, and 3.6 g/d; 7 d 12 Inhibited inflammation and DNA damage [24
 1.08 g/d; 10–30 d 26 Improved general health [25
 2 or 4 g/d; 30 d 44 Reduction in ACF number (40%) [26
 2.35 g/d; 14 d 26 Recovery of high levels of curcumin [27
HNSCC 2 g once 39 Decreased IKKβ kinase activity in saliva [28
Pancreatic cancer 8 g/d; 8 w 25 Safe, well tolerated, and efficacious [29
 8 g/d; 4 w 17 Partial response and stable disease [30
 8 g/d; 14 d every 3 w 21 Safe and well tolerated [31
 0.2–0.4 g; 9 m 16 Safe and well tolerated [32
Prostate cancer 100 mg/d; 6 m 85 Reduced serum PSA levels [33
 3 g/d; 3 m 40 No significant effect [34
Solid tumours 3 × 100 mg; 4 m* 160 Reduced side effects of cancer treatment [35
 180 mg/d; 8 w 80 Improved quality of life [36
CancerDose of curcuminPatientsClinical outcomeReference
BPH 1 g/d; 24 w 61 Reduced signs and symptoms of disease [16
Breast cancer 6 g/d; 7 d 14 Safe and well tolerated [17
Cancerous lesions Ointment 62 Reduced lesion size and pain [15
 0.5–1.2 g/d; 3 m 25 Well tolerated and efficacious [18
Cervical cancer 500 mg/d; 30 d 280 Enhanced HPV clearance rate [19
CML 3 × 5 g; 6 w 50 Decreased nitric oxide levels [20
Colorectal cancer P54FP/d; 29 d 15 Inhibited basal and LPS-induced PGE2 [21
 2.2 g/d; 4 m 15 Well tolerated [22
 0.45 and 3.6 g/d; 4 m 15 Well tolerated and efficacious [23
 0.45, 1.8, and 3.6 g/d; 7 d 12 Inhibited inflammation and DNA damage [24
 1.08 g/d; 10–30 d 26 Improved general health [25
 2 or 4 g/d; 30 d 44 Reduction in ACF number (40%) [26
 2.35 g/d; 14 d 26 Recovery of high levels of curcumin [27
HNSCC 2 g once 39 Decreased IKKβ kinase activity in saliva [28
Pancreatic cancer 8 g/d; 8 w 25 Safe, well tolerated, and efficacious [29
 8 g/d; 4 w 17 Partial response and stable disease [30
 8 g/d; 14 d every 3 w 21 Safe and well tolerated [31
 0.2–0.4 g; 9 m 16 Safe and well tolerated [32
Prostate cancer 100 mg/d; 6 m 85 Reduced serum PSA levels [33
 3 g/d; 3 m 40 No significant effect [34
Solid tumours 3 × 100 mg; 4 m* 160 Reduced side effects of cancer treatment [35
 180 mg/d; 8 w 80 Improved quality of life [36

Abbreviations: d, days; HNSCC, head and neck squamous cell carcinoma; HPV, human papillomavirus; m, months; PGE2, prostaglandin E2; w, weeks; y, years; *, curcumin formulation; , combination; , turmeric.

Table 3
Ongoing clinical trials of curcumin in different cancers
CancerDosePatientsPhaseAffiliationStart date
ADH 50 and 100 mg; 3 m 30  - Lisa Yee; OSU, U.S.A. June, 2013 
Breast cancer 500 mg II Andrew Mille; Emory University, U.S.A. May, 2015 
 Curcumin gel; 4–6 hrs* 180 II Gary Morrow, URCC NCORP October, 2015 
Cancer 200 mg/d; 28 d 28 David Hong; MDACC, U.S.A. October, 2011 
 100–300 mg/M2; 8 w* I/II Richard Greil; Internistische Onkologie March, 2014 
 Curcumin 40 Aminah Jatoi; Mayo Clinic March, 2016 
CIN 1000 mg/d; 12 w 14 Carolyn Matthews; Texas Oncology March, 2016 
Colon cancer Curcumin 100 III Arie Figer; TASMC, Israel March, 2006 
 4g/d; 30 d* 40 Gary Asher; UNC-CH, U.S.A. November, 2010 
 Curcumin; 7 d 35 Donald Miller; JGBCC, U.S.A. January, 2011 
 2–4 g/d; 6 y 51 I/II William Steward; UHL, U.K. February, 2012 
 1–4 g/d; 4 d 20 Gary Asher; UNC-CH, U.S.A. June, 2013 
 0.5 and 1 g/d; 28 d* 100 II Andrea DeCensi; Ente Ospedaliero Ospedali Galliera March, 2014 
 100 mg/d 44 II Jeong-Heum Baek; Gachon University May, 2015 
 1000 mg/d; 2 w 14 John Preskitt; Texas Oncology, PA March, 2016 
EC 2 g/d; 2 w* 10 II Frederic Amant; UZ, Belgium October, 2013 
Glioblastoma Curcumin 15 Stephan Duetzmann; Goethe University Germany October, 2012 
H&NC 8 g/d; 21–28 d 33 Cherie-Ann Nathan; LSUHSC, U.S.A. June, 2010 
Lymphoma Curcumin 35 II Paolo Caimi Case; CCC, U.S.A. September, 2014 
NSCLC 80 mg/d; 8 w* 20 Victor Cohen; LDI, Canada August, 2015 
Osteosarcoma Curcumin powder 24 I/II Manish Agarwal; TMH, India May, 2008 
Prostate cancer Curcumin 100 II Centre Jean Perrin March, 2014 
 120 mg/d; 3 d* 64 II Abolfazl Razzaghdoust; SBUMS, Iran March, 2016 
Rectal cancer 8 g/d 45 II Sunil Krishnan; MDACC, U.S.A. August, 2008 
CancerDosePatientsPhaseAffiliationStart date
ADH 50 and 100 mg; 3 m 30  - Lisa Yee; OSU, U.S.A. June, 2013 
Breast cancer 500 mg II Andrew Mille; Emory University, U.S.A. May, 2015 
 Curcumin gel; 4–6 hrs* 180 II Gary Morrow, URCC NCORP October, 2015 
Cancer 200 mg/d; 28 d 28 David Hong; MDACC, U.S.A. October, 2011 
 100–300 mg/M2; 8 w* I/II Richard Greil; Internistische Onkologie March, 2014 
 Curcumin 40 Aminah Jatoi; Mayo Clinic March, 2016 
CIN 1000 mg/d; 12 w 14 Carolyn Matthews; Texas Oncology March, 2016 
Colon cancer Curcumin 100 III Arie Figer; TASMC, Israel March, 2006 
 4g/d; 30 d* 40 Gary Asher; UNC-CH, U.S.A. November, 2010 
 Curcumin; 7 d 35 Donald Miller; JGBCC, U.S.A. January, 2011 
 2–4 g/d; 6 y 51 I/II William Steward; UHL, U.K. February, 2012 
 1–4 g/d; 4 d 20 Gary Asher; UNC-CH, U.S.A. June, 2013 
 0.5 and 1 g/d; 28 d* 100 II Andrea DeCensi; Ente Ospedaliero Ospedali Galliera March, 2014 
 100 mg/d 44 II Jeong-Heum Baek; Gachon University May, 2015 
 1000 mg/d; 2 w 14 John Preskitt; Texas Oncology, PA March, 2016 
EC 2 g/d; 2 w* 10 II Frederic Amant; UZ, Belgium October, 2013 
Glioblastoma Curcumin 15 Stephan Duetzmann; Goethe University Germany October, 2012 
H&NC 8 g/d; 21–28 d 33 Cherie-Ann Nathan; LSUHSC, U.S.A. June, 2010 
Lymphoma Curcumin 35 II Paolo Caimi Case; CCC, U.S.A. September, 2014 
NSCLC 80 mg/d; 8 w* 20 Victor Cohen; LDI, Canada August, 2015 
Osteosarcoma Curcumin powder 24 I/II Manish Agarwal; TMH, India May, 2008 
Prostate cancer Curcumin 100 II Centre Jean Perrin March, 2014 
 120 mg/d; 3 d* 64 II Abolfazl Razzaghdoust; SBUMS, Iran March, 2016 
Rectal cancer 8 g/d 45 II Sunil Krishnan; MDACC, U.S.A. August, 2008 

Abbreviations: ADH, atypical ductal hyperplasia; CIN, cervical intraepithelial neoplasia; d, days; EC, endometrial carcinoma; H&NC, head and neck cancer; m, months, w, weeks; y, years; *, curcumin formulation; , combination.

Thus, curcumin has gained a great deal of attention among the therapeutic cache in oncology due to its potent effect against diverse cancers through modulation of multiple cell signaling pathways, which include members of epidermal growth factor receptors (EGFR and erbB2), sonic hedgehog (SHH)/GLIs, Wnt/β-catenin, various downstream signaling elements such as Akt, NF-κB, and STATs as well as different metastatic and angiogenic pathways, as shown in many preclinical and clinical studies (Figure 2) [3841]. In this review, we discuss the cancer-related signaling pathways that are modulated by curcumin and how the modulation of cell signaling molecules leads to its chemopreventive and therapeutic activities against numerous cancers.

Multiple signaling pathways modulated by curcumin

Figure 2
Multiple signaling pathways modulated by curcumin

Abbreviations: AP-1, activating protein-1; EGR-1, early growth response protein-1; ERE, estrogen response element; HIF-1, hypoxia-inducible factor-1; mTOR, mammalian target of rapamycin; ncRNAs, non-coding RNAs; Nrf2:,NF-E2-related factor 2; PI3K/AKT, phosphatidylinositide 3-kinases/protein kinase B; STAT3, signal transducer and activator of transcription 3; WT1: Wilms’ tumor 1.

Figure 2
Multiple signaling pathways modulated by curcumin

Abbreviations: AP-1, activating protein-1; EGR-1, early growth response protein-1; ERE, estrogen response element; HIF-1, hypoxia-inducible factor-1; mTOR, mammalian target of rapamycin; ncRNAs, non-coding RNAs; Nrf2:,NF-E2-related factor 2; PI3K/AKT, phosphatidylinositide 3-kinases/protein kinase B; STAT3, signal transducer and activator of transcription 3; WT1: Wilms’ tumor 1.

Cell signaling pathways modulated by curcumin

NF-κB pathway

NF-κB is a proinflammatory transcription factor that was first discovered by Ranjan Sen and David Baltimore in 1986 [42]. Over 500 different genes have shown to be regulated by NF-κB and to control the expression of proteins linked to a variety of cell signaling pathways leading to tumorigenesis and inflammation [43]. The aberrant activation of NF-κB plays a major role in the pathogenesis of several types of cancer [4447]. Therefore, agents that can disrupt NF-κB activation pathways have high potential in cancer therapy. Curcumin is one such agent that has been shown to disrupt several steps of the NF-κB activation pathway.

Our group was the first to provide scientific evidence that curcumin suppressed TNF-α-induced nuclear translocation and DNA binding of NF-κB through suppression of IκBα phosphorylation and degradation in the human myeloid leukemia cell line [48]. Curcumin inhibited IκB degradation through down-regulation of NF-κB-inducing kinase (NIK) and IκB kinase (IKK). This nutraceutical exhibited antiproliferative, proapoptotic, and antimetastatic activities in multiple myeloma [49] and murine melanoma cells [50] through suppression of IKK activity. Subsequently, many groups have shown that curcumin inhibited cancer cell proliferation, survival, invasion, metastasis, chemoresistance, radioresistance, and angiogenesis of various cancers by modulating different targets that are regulated by NF-κB. For instance, curcumin has been shown to inhibit the proliferation and survival of pancreatic cancer cells in vitro and in vivo through inhibition of NF-κB, COX-2, CD-31, VEGF, and IL-8 [51]. In another study, curcumin was reported to restrain the growth and induce apoptosis of colon cancer cells through suppression of genes such as NF-κB (p65 and p50), specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4 and Sp-regulated genes, hepatocyte growth factor receptor (c-MET), survivin, BCL-2, and cyclin D1 [52]. In an orthotopic mouse model of colorectal cancer, curcumin inhibited NF-κB activation and sensitized cancer cells to capecitabine [53]. Furthermore, curcumin inhibited the expression of cyclin D1, COX-2, matrix metalloproteinase (MMP)-9, VEGF, and CXC chemokine receptor 4 (CXCR4), which may be a result of its inhibitory effect on NF-κB activation. Treatment with curcumin also caused inhibition of tumor growth and angiogenesis in ovarian cancer via modulation of NF-κB pathway [54]. It was found to inhibit acrylamide-induced proliferation of HepG2 cells and expression of NF-κB, CYP2E1, EGFR, and cyclin D1 [55]. In line with other studies, NF-κB signal transduction pathway was also targeted in cases of curcumin-treated Raji cells. Down-regulation of NF-κB was mediated via a component of HDACs and p300/Notch1 signal molecules [56]. The administration of curcumin on prostate cancer cells stimulated the repression of androgen receptors and androgen receptor-related cofactors, including NF-κB [57]. The therapeutic potential of curcumin in lung cancer cells was also mediated via down-regulation of NF-κB [58]. A similar effect was observed in breast cancer that led to the inhibition of TPA-induced MMP-9 expression and cell invasion [59].

The anticancer activities of curcumin through the inhibition of NF-κB activities have been demonstrated by clinical trials in cancer patients. For example, oral administration of curcumin was found to suppress NF-κB in PBMC from multiple-myeloma patients [60]. Furthermore, curcumin, either alone (up to 12 g/d) or in combination with bioperine for 12 weeks, was well tolerated by the patients. Curcumin has also been shown to be well tolerated and to suppress NF-κB activity in patients with advanced pancreatic cancer [29]. This polyphenol has also been shown to suppress IKKβ kinase activity in the salivary cells of patients with HNSCC [61]. Overall, these studies suggest that this compound exhibits anticancer activities and can suppress NF-κB activation in cancer patients. However, further studies in this area are required.

STAT3 pathway

STAT3 is a proinflammatory transcription factor that plays a major role in the pathogenesis of various cancers. STAT3 is constitutively expressed in several cancer types and is reported to modulate tumorigenic proteins [62]. The activation of STAT3 has also been linked with chemoresistance and radioresistance [63] and with decreased survival of cancer patients [62]. Thus, STAT3 is an attractive therapeutic target for the development of anticancer agents, and agents with the potential to inhibit STAT3 activation would have anticancer potential.

Curcumin has been shown to inhibit STAT3 activation in cell lines, animal models, and clinical studies. Our laboratory was the first to demonstrate the inhibitory effects of curcumin on STAT3 pathways. We have shown that this compound inhibited both constitutive and inducible STAT3 activation in human multiple myeloma cells [49]. In gastric cancer cells, curcumin, either alone or in combination with 5-fluorouracil (5-FU), has been shown to inhibit the phosphorylation of STAT3 and its viability in a dose-dependent manner, thus reducing the chemoresistance of gastric cancer cells [64]. Curcumin has also been shown to sensitize HNSCC cells to cisplatin by suppressing STAT3 phosphorylation [65].

It also reduces tumor spheres of H460 cells via inhibition of the JAK2/STAT3 signaling pathway [66], which is suggestive of its potential against lung cancer stem cells. Furthermore, suppression of STAT3 activation by curcumin led to the reduced invasion of skin squamous carcinoma cells [67]. The intraperitoneal administration of curcumin has also been shown to reduce STAT3 phosphorylation in tumor-bearing mice [68]. In a dextran sulfate sodium (DSS)-induced mouse colitis model, oral administration of curcumin reduced colitis significantly via inhibition of STAT3 signaling [69]. This compound also inhibited tumor growth in an orthotopic murine model of ovarian cancer through inhibition of STAT3 activation [54]. Additionally, curcumin treatment resulted in the inhibition of STAT3 activation in patients with pancreatic cancer [29] and multiple myeloma [60].

PI3K/AKT/mTOR pathway

Akt, also known as protein kinase B (PKB) is involved in different cellular processes that are critical for diverse cell functions. Interestingly, alterations in Akt, including mutation and amplification, are linked with carcinogenesis [70]. The mTOR is a kinase that also plays a crucial role in the regulation of cell growth and the progression of the cell cycle. Various upstream activators and downstream effectors of mTOR are found to be dysregulated during malignancy [71].

Curcumin has been shown to exhibit remarkable antiapoptotic effects in different malignancies through modulation of PI3K/Akt/mTOR signaling [72]. In a recent study, curcumin was found to inhibit proliferation and induce apoptosis in human NSCLC cells through the suppression of PI3K/Akt and the up-regulation of miR-192-5p [73]. The polyphenol also inhibited lung tumor proliferation induced by neutrophil elastase through enhanced α1-antitrypsin expression both in vitro and in vivo via the PI3K/Akt pathway [74]. Furthermore, catanionic lipid nanosystems incorporating curcumin were found to induce significant apoptosis in Lewis lung cancer (LLC) cells through the PI3K/Akt/FoxO1/Bim pathway [75]. Treatment with another novel curcumin analog, (E)-2-(4-hydroxy-3-methoxybenzylidene)-5-((E)-3-(4-hydroxy-3-methoxyphenyl)acryloyl) cyclopentanone (CUR3d), also resulted in controlling the growth of HepG2 hepatocellular carcinoma cells via down-regulation of PI3K/Akt (Akt1, Akt2) [76]. In breast cancer cells, curcumin was shown to down-regulate Akt protein in a dose- and time-dependent manner together with induction of autophagy and suppression of the ubiquitin–proteasome pathway [77]. Furthermore, blocking the PI3K/Akt signaling pathway by curcumin has been hypothesized to enhance apoptosis and autophagy in breast cancer cells [78]. Another study found that the different modulation of the PI3K/Akt–SKP2–Cip/Kips signaling pathway was strongly involved in the differential susceptibilities of MCF-7 and MDA-MB-231 breast cancer cells [79]. Administration of curcumin inhibited the growth of breast cancer cells through the down-regulation of pAkt and MAPK [80]. Additionally, administering curcumin with PI3K inhibitor was found to produce synergistic effects on apoptosis in MCF-7 cells [73]. In pancreatic cancer cells, curcumin was found to induce FoxO1 expression by inhibiting PI3K/Akt signaling, which in turn led to cell cycle arrest and apoptosis induction [81]. In another study, curcumin inhibited proliferation and induced apoptosis through inhibition of PI3K/Akt signaling and up-regulation of PTEN [82]. Curcumin also caused marked inhibition of growth, migration, and invasion of thyroid cancer cells through down-regulation of Akt signaling and subsequent attenuation of MMP1/7 and COX-2 proteins [83]. In colon cancer cells, curcumin caused notable inhibition in the cell growth and migration and also led to the induction of apoptosis through suppression in Akt phosphorylation and up-regulation of caspase-3, cytochrome c, and Bax mRNA [84]. Curcumin has also been shown to exhibit a potent radiosensitizing effect through inhibition of the PI3K/Akt/mTOR pathway in gut-specific endothelial cells [85]. The PI3K/Akt signal transduction pathway is commonly reported to be misregulated in lymphoma and is often linked with tumorigenesis and increased radiotherapy resistance. In a study conducted by Qiao and colleagues, curcumin was found to inhibit the constitutive and radiation-induced expression of the PI3K/Akt in human Burkitt’s lymphoma cells [86]. Curcumin exhibited a suppressive effect on the cellular melanin contents and the tyrosinase activity in α-MSH-stimulated melanoma cells through down-regulation of microphthalmia-associated transcription factor (MITF) and its downstream signal molecules via activation of PI3K/Akt [87]. In addition, curcumin has been found to reverse the mechanism of multi-drug resistance (MDR), possibly through down-regulation of P-gp and inhibition of the PI3K/Akt/NF-κB pathway [88]. Curcumin together with FOLFOX resulted in decreased survival of colon cancer cells, which was accompanied by reduced Akt, EGFR, HER-2, and IGF-1R activation, together with expression of COX-2 and cyclin-D1 [89].

Curcumin has also been shown to inhibit proliferation and invasion and to induce G2/M-cell cycle arrest and autophagy in melanoma cells through suppression of Akt, mTOR, and P70S6K proteins both in vitro and in vivo settings [90]. In prostate cancer cells, curcumin abolished cancer-associated fibroblast (CAF)-induced invasion and epithelial–mesenchymal transition (EMT) and blocked the production of reactive oxygen species (ROS) as well as the expression of CXCR4 and IL-6 receptor [91]. The polyphenol also reduced uterine leiomyosarcoma tumor growth in vivo through reduction of mTOR and S6 phosphorylation [92]. Furthermore, curcumin can also inhibit nicotine-associated adverse reactions through blockage of nicotine-induced activation of Akt/mTOR pathway in HNSCC cells [93]. Moreover, it reduced the effect of irradiation-induced prosurvival signaling via the modulation of PI3K/Akt/mTOR and NF-κB pathways in gut-specific endothelial cells indicating curcumin’s potent radiosensitizing potential in colorectal cancer [85]. In addition, curcumin was found to potentiate the efficacy of imatinib in ALL cells through the down-regulation of the Akt/mTOR pathway and the expression of BCR-ABL [94]. In non-Hodgkin’s lymphoma cells, curcumin could improve the cell response to ionizing radiation through G2/M-cell cycle arrest and the inhibition of mTOR–NF-κB pathway [86]. Combined administration of curcumin and EGCG reduced uterine leiomyosarcoma cell growth and induced apoptosis, mediated through inhibition of Akt, mTOR, and S6 phosphorylation [95]. Curcumin’s efficacy against uterine leiomyosarcoma cells through the inhibition of the Akt-mTOR pathway has been reported by another study [96].

Apart from individual treatment, combined administration of curcumin with docetaxel and nelfinavir also caused significant suppression of phosphorylated-Akt and induction in phosphorylated-eIF2α in castration-resistant prostate cancer cells [97]. In another study, curcumin, along with all-trans retinoic acid (ATRA), was found to induce differentiation of NB4-R1 cells through enhanced phosphorylation of Akt [98]. The combined treatment of curcumin with 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) has been reported to be a novel strategy against melanoma through the inhibition of the PI3K/Akt signaling [99].

EGFR pathway

EGFR, a family of receptor tyrosine kinases, is a complex signal transduction cascade that is involved in the modulation of cell proliferation, survival, adhesion, migration, and differentiation [100]. EGFR is regarded as a vital target for cancer therapy. Curcumin causes direct but partial inhibition of the enzymatic activity of EGFR’s intracellular domain. The polyphenol was also found to influence EGFR’s cell membrane environment [101].

Curcumin’s potential to inhibit the growth, invasion, and metastasis of diverse cancer cells via the down-regulation of EGFR expression is well documented. For instance, in brain cancer, curcumin exhibited potent modulatory effects on the growth and viability of LN229 cells by elevating the cytostatic and/or cytotoxic effect of selective EGFR kinase inhibitors, namely AG494 and AG1478 tyrphostins [102]. Furthermore, curcumin decreased the expression and phosphorylation of EGFR in gefitinib-resistant lung adenocarcinoma cells [103]. Another study evaluated the effect of curcumin on the tumor growth of erlotinib-resistant NSCLC cells [104]. In this study, curcumin was found to elevate the cytotoxic and apoptosis-inducing potential of erlotinib through down-regulation of EGFR, p-EGFR, survivin and through inhibition of NF-κB activation [104]. The administration of curcumin was also found to suppress the expression of COX-2, EGFR, and extracellular signal-regulated kinase (ERK)1/2 activities, which correlated with elevated apoptosis and reduced survival of lung and pancreatic adenocarcinoma cells [105]. Moreover, curcumin exhibited an antiproliferative and anti-invasive effect on oral squamous cell carcinoma via inhibition of EGFR phosphorylation and its downstream targets such as Akt, ERK1/2, and STAT3 [106]. In another study, curcumin was found to possess potential for inhibiting proliferation and for the invasion of oral cancer cells through modulation of multiple targets including EGFR [107]. Curcumin has also been shown to improve the efficacy of radiation both in vitro and in vivo via suppression of EGFR phosphorylation and COX-2 expression in SCC-1 cells [108]. At high doses, it can inhibit tumor growth and angiogenesis in mice bearing cervical cancer cells, possibly through the down-regulation of EGFR, VEGF, and COX-2 [109]. In mouse hepatocellular carinoma cells, curcumin was found to inhibit migration and invasion in a concentration- and time-dependent manner by inactivating the EGFR and Cav-1 pathways [110]. In colon cancer cells, curcumin was found to inhibit cell growth inhibition and induced apoptosis through down-regulation of EGFR and other proteins [58]. This polyphenol also inhibited the growth of human colon cancer cells by down-regulating EGFR via decreased EGR-1 trans-activation activity [111]. Curcumin also inhibited the proliferation of triple-negative breast cancer cells that were accompanied by reduced EGFR signaling [112]. Curcumin also suppressed the growth of breast cancer cells by attenuating the levels of EGFR and Akt [113]. In ovarian cancer cells, curcumin reduced AQP3 expression and cell migration through inhibition of EGFR and inactivation of Akt/ERK signaling [114]. Moreover, in bladder cancer cells, curcumin suppressed EGFR expression [115]. Additionally, curcumin was shown to inhibit α6β4 signaling and function by inducing alterations in its intracellular localization, which in turn led to the dissociation of α6β4 with EGFR signaling [116]. Furthermore, combined administration of curcumin with doxorubicin (DOX) or 5-FU led to the inhibition of HNSCC cell proliferation via the down-regulation of EGFR–ERK1/2 [117]. In addition, curcumin together with paclitaxel synergistically inhibited growth and induced apoptosis in breast cancer cells by blocking EGFR signaling and modulating Bax, BCL-2 expression [118]. Curcumin potentiated the antitumor effect of gefitinib in NCSLC both in vitro as well as in vivo, which was mediated through inhibition of proliferation and EGFR phosphorylation, and induction of EGFR ubiquitination and apoptosis [119]. Furthermore, a combined regimen of curcumin and small molecule inhibitors including those against EGFR exerts a potent growth inhibitory effect, implying that this polyphenol can be used as an adjuvant therapy against NSCLC [120]. Curcumin in combination with FOLFOX resulted in an antisurvival effect on colon cancer cells along with a notable decrease in EGFR, HER-2, IGF-1R, and Akt activation and down-regulation of COX-2 and cyclin D1 expression [89]. In combination with resveratrol, curcumin exhibited a synergistic effect that was accompanied by a marked inhibition of EGFR activation and IGF-1R in a SCID xenograft model bearing colon cancer cells [121]. Apart from these, the combination of curcumin with β-phenylethyl isothiocyanate was also shown to inhibit EGFR signaling, which ultimately led to inhibition of proliferation as well as the programmed cell death of prostate cancer cells [122].

Nrf2 pathway

The transcription factor Nrf2 is a key regulator of a variety of genes that are involved in the detoxification of electrophiles and ROS and the repair or removal of some of their damage products. In recent years, Nrf2 has emerged as a potent target for cancer chemoprevention [123].

Curcumin’s chemopreventive and antiproliferative potential through modulation of the Nrf2 pathway has also been demonstrated by a number of studies. For example, curcumin has been shown to possess chemopreventive potential through activation of the Nrf2 pathway, restoration of p53, and modulation of inflammatory molecules in vivo [124]. Furthermore, knockdown of Nrf2 reduced the anti-inflammatory effects of curcumin [125]. In another study, the antiproliferative potential of curcumin against breast cancer cells was mediated through modulation of the Nrf2 pathway [126]. It was also found to exert prostate cancer chemoprevention partially via epigenetic modification of the Nrf2 gene and induction of Nrf2-mediated antioxidative stress cellular defense pathway [127]. In addition, curcumin exerted chemosensitization against cisplatin by reducing tumor proliferation via modulation of pSTAT3 and Nrf2 pathways in case of HNSCC both in vitro and in vivo [65]. In another study, curcumin in combination with cisplatin exhibited potent synergistic effects on bladder carcinoma cells through down-regulation of the Keapl–Nrf2 pathway [128].

Notch 1 pathway

Notch 1 belongs to the Type 1 transmembrane protein of the Notch family. Notch family members play a significant role as a deciding factor between cell differentiation, proliferation, or apoptosis. Being dysregulated in multiple cancer types, Notch 1 has been used as a therapeutic target for cancer therapy [129]. Curcumin has been shown to down-regulate Notch 1 in multiple cancer types such as oral, esophageal, and colorectal cancers. Furthermore, curcumin was found to inhibit Notch 1 either alone or in combination with other agents.

Curcumin inhibited the proliferation of Raji cells notably, and repressed NF-κB signal transduction cascade through p300/Notch 1 signal molecules and different HDACs components [56]. In case of esophageal cancer, treatment with curcumin resulted in decreased activation of Notch 1 via down-regulation of vital components of the γ-secretase complex proteins such as Presenilin 1 and Nicastrin. [130]. The Notch signaling pathway has been reported to play a significant role in cancer stem cells, and the inhibition of Notch by curcumin is known to inhibit the growth of cancer stem cells [131,132]. Not only curcumin, but also its synthetic analog, difluorinated curcumin (CDF), suppressed Notch 1 pathway [133].

Wilms’ tumor 1 pathway

The WT1 gene acts like a double-edged sword: oncogene and tumor suppressor gene and plays an important role in the proliferation and survival of various cancer cells [134,135]. WT1 was found to be highly expressed in many leukemic cell lines as well as in acute myeloid leukemia patients. Treatment with curcumin inhibited the expression of WT1 protein, which in turn attenuated the proliferation and clonogenicity of leukemic cells [134]. Curcumin also down-regulated WT1 mRNA expression in leukemic cells in patients [136]. Furthermore, curcumin mediated down-regulation of WT1 through up-regulation of miR-15a/16-1 in leukemic cells [137]. In K562 cells, curcumin was found to significantly reduce the transcripts of WT1 and bcr/ablp210 genes, which ultimately led to the inhibition of cell proliferation and G(2)/M-cell cycle arrest [138]. In another study, curcumin was shown to reduce the expression of WT1 both at the transcriptional and translational level in leukemia cells [139]. While WT1 is frequently expressed in pancreatic cancer cells, administration of curcumin inhibited pancreatic cancer growth through down-regulation of WT1. Moreover, co-treatment of curcumin with WT1 siRNA was associated with enhanced inhibition of WT1 signaling as compared to that observed with either of them alone [135].

Activating protein-1 pathway

AP-1 is a collective term referring to dimeric transcription factors composed of Jun, Fos, or activating transcription factor (ATF) subunits that bind to a common DNA site, as the AP-1-binding site [140]. AP-1 is involved in cellular proliferation, transformation, and death [141]. Curcumin was found to modulate AP-1 in different cancers. Nakamura et al. evaluated the effects of curcumin on cell growth, activation of signal transduction, and transforming activities of both androgen-dependent and -independent cell lines, and found down-regulation of transactivation and expression of AR, AP-1, NF-κB, and cAMP response element-binding protein-binding protein (CBP) upon treatment with curcumin [57]. Another study showed a similar result where curcumin exerted an antitumor effect against androgen-independent prostate cancer cells by inhibiting cellular proliferation and inducing apoptosis [142]. Another study carried out in a lymphoma-bearing mice showed curcumin to attenuate carcinogenesis by down-regulating proinflammatory cytokine IL-1α and IL-1β via modulation of AP-1 and IL-6 [143]. Curcumin pretreatment impeded formaldehyde-induced oxidative stress, ameliorated DPCs, and impaired activation of AP-1 in A549 cell lines [58]. In another study, curcumin has been shown to inhibit TPA-induced MMP-9 expression, cell invasion, and suppressed PKCα, MAPK, and NF-κB/AP-1 pathway in MCF-7 cells [59]. Curcumin-induced apoptosis of THP-1 cells through AP-1 activation highlighting its huge potential as a novel antitumor agent in acute monocytic leukemia cells [144]. In addition, it has been shown that this compound blocked miR-21 transcriptional regulation via AP-1, repressed cell proliferation, tumor growth, invasion, in vivo metastasis, and stabilized the expression of the tumor suppressor Pdcd4 in colorectal cancer [145].

HIF-1 pathway

HIF-1 is a heterodimeric transcription factor consisting of α and β subunits, where the β-subunit is constitutively expressed and the α-subunit is regulated by oxygen [146148]. HIF-1 leads to transcriptional activation of several genes strongly involved in vital aspects of cancer development, including angiogenesis, cell survival, glucose metabolism, and invasion [149]. This transcription factor is required for continued survival of cancer cells as it takes part in glycolysis activation. It essentially provides aid to oxygen-starved cells in converting sugar to energy without utilizing oxygen and also initiates angiogenesis [150]. HIF-1α contributed to drug resistance in cancer cells and, hence, targeting HIF-1α either by RNAi or siRNA can overpower resistance against chemotherapeutic drugs. Therefore, HIF-1α is a potent and prospective target in cancer therapeutics. Curcumin has been shown to suppress tumor growth by inhibiting HIF-1α-mediated angiogenesis [151]. In pituitary adenomas, curcumin blocked the induction of HIF-1α mRNA synthesis and protein production by degrading aryl hydrocarbon receptor nuclear translocator leading to tumor growth inhibition [152,153]. In another study, it was shown that curcumin treatment down-regulated HIF-1α, which became remarkably up-regulated in areca quid chewing-associated OSCC [154]. In addition, it has been shown that combinatorial treatment of curcumin and DDP inhibited the proliferation of A549/DDP cells, reversed DDP resistance, and stimulated apoptotic death by fostering degradation of HIF-1α and caspase-3 activation [155].

Wnt/β-catenin pathway

The Wnt/β-catenin pathway plays a pivotal role in the regulation of cell proliferation, survival, and apoptosis. The dysregulation of the components of this pathway have been found to be associated with various diseases, including cancer [156]. Several studies reported curcumin to function through the modulation of Wnt/β-catenin signaling pathway in different cancer types. For example, Prasad and colleagues showed that treatment of MCF-7 and MDA-MB-231 cells with curcumin inhibited Wnt/β-catenin signaling and altered the expression of c-Myc, cyclin D1, GSK3β, and E-cadherin [157]. Curcumin has also been shown to inhibit the migration of breast cancer stem cells by restoring E-cadherin expression, thereby causing enhanced E-cadherin–β-catenin complex formation [158]. Furthermore, the effect of curcumin was evaluated on ER-negative human breast cancer cells by exposing them to heterocyclic cyclohexanone curcumin derivatives where a transient increase in the level of β-catenin was observed [159]. In cases of prostate cancer, curcumin treatment resulted in decreased cell proliferation, colony formation, cell motility, and enhanced cell–cell aggregation via modulation of nuclear β-catenin transcription activity as well as membrane β-catenin levels [160]. It was also observed to interject in the interaction between the Wnt/β-catenin signaling pathway and androgen receptors in LNCaP prostate cancer cells [161]. Another study investigated the potential of curcumin-loaded nanoparticles, PLGA–CUR NPs (poly (lactic-co-glycolic acid–CUR nanoparticles) against prostate cancer and found that they exhibited marked anticancer activity via inhibition of β-catenin expression [162]. In lung cancer, curcumin inhibited the proliferation and invasion of NSCLC cells and induced G0/G1-phase arrest by MTA1-mediated inactivation of Wnt/β-catenin pathway [163]. In colon cancer, treatment of curcumin was shown to inhibit β-catenin/Tcf-4 signaling cascade together with reduced expression of peroxisome proliferator-activated receptor delta, 14-3-3 epsilon, and VEGF and was found to cause G(2)/M-phase arrest and apoptosis through the induction of caspase-3-mediated degradation of cell–cell adhesion proteins β-catenin [164,165]. Furthermore, curcuminoids were found to inhibit JMJD2C, a histone demethylase, which forms complexes with β-catenin and whose overexpression plays a vital role in most colonic tumor development, thus indicating a potent adjuvant therapy for the treatment of colon cancer [166]. Another major metabolite of curcumin, tetrahydrocurcumin (THC) has been demonstrated to exhibit anticarcinogenic and antiangiogenic effect in colon carcinogenesis in vivo, mediated via a reduction in the expression of azoxymethane-induced Wnt-1 and β-catenin proteins in colonic tissue [167]. The nanopolymeric curcumin (PNCC) also exerted a significant chemopreventive effect on azoxymethane-initiated colon cancer through inhibition of cell proliferation and induction of apoptosis in an azoxymethane-induced rat tumor via reduced expression of β-catenin proteins [168].

EGR-1 pathway

EGR-1, also known as nerve growth factor- induced protein A, plays vital role in regulating growth, differentiation, and apoptosis in many cell types via the regulation of over 30 genes [169]. Most studies report EGR-1 as a tumor suppressor gene as it has been found to induce the expression and secretion of multiple tumor suppressor genes including TGFβ1, PTEN, p53, and fibronectin. However, it functions as an activator in the absence of overlapping Sp-1 binding sequences [169,170]. Curcumin induced the expression of EGR-1 through the modulation of ERK and c-Jun NH(2)-terminal kinase (JNK), which in turn activated the transcription of p21 (Waf1/Cip1) and led to tumor suppression [171,172]. Its treatment induced growth arrest and apoptosis of B-cell lymphoma via the down-regulation of egr-1, c-myc, and bcl-X(L) and p53 in B cells [173]. In addition, curcumin treatment inhibited the growth of human colon cancer cells through suppression of EGFR, which was found to be mediated by decreased Egr-1 transactivation [111].

Non-coding RNAs

While less than 2% of the entire human genome sequence accounts for protein-coding genes, the remaining 98% are non-coding sequences. However, 90% of these non-coding sequences are transcribed, producing a large number of ncRNAs. These ncRNAs include well-characterized microRNAs (18–22 nucleotide long) and recently discovered long non-coding RNAs (lncRNAs) that are more than 200 nucleotides long. The ncRNAs are dysregulated in a number of disease conditions including cancer [174176]. Since ncRNAs possess both oncogenic and tumor suppressor function [177,178], several strategies have been adopted to target ncRNAs including the use of pharmacological inhibitors.

The potential of curcumin in modulating miRNA expression has been well established by several laboratories. In particular, this polyphenol has been shown to either down-regulate oncogenic microRNAs or up-regulate tumor-suppressive microRNAs [179]. For example, curcumin can up-regulate miRNA-22 in pancreatic cancer cells [180]. The common miRNAs known to be down-regulated by curcumin treatment include miRNA-199a in pancreatic cancer cells [180], miRNA-186 in lung carcinoma cells [181], and miRNA-21 in colorectal cancer cells [145]. CDF was found to up-regulate miRNA-200b and miRNA-200c and down-regulate miRNA-21 in gemcitabine-sensitive and -resistant pancreatic cancer cells [182].

Although the potential of curcumin in modulating miRNA expression is well documented, only a little is known about its role in modulating the expression of lncRNAs. The dendrosomal curcumin (DNC) was found to induce MEG3 in hepatocellular carcinoma, which is a tumor-suppressor lncRNA [183]. Similarly, curcumin has been shown to inhibit the migration of RCC cells through the suppression of HOX transcript antisense RNA (HOTAIR) [184]. Curcumin can also radiosensitize nasopharyngeal carcinoma (NPC) cells through modulation of lncRNAs [185].

In conclusion, curcumin has been shown to modulate the expression of ncRNAs that can contribute to its anticancer activities. However, the potential of this polyphenol in modulating ncRNA expression in clinically relevant animal models and cancer patients is not known and should be carried out in future.

Other pathways modulated by curcumin

Apart from the aforementioned, there are several other signaling pathways that have been well documented to contribute toward the antiproliferative and chemopreventive efficacy of curcumin. For example, in human colorectal cancer, PGE2, which activates the Ras/Raf/ERK pathway, was found to reverse curcumin-induced inhibition of survival signal pathways [186]. Again, HDAC inhibition mediated via curcumin could suppress the DNA damage response and aid in the enhanced sensitivity toward DNA damage [187]. ERE also acted as an important therapeutic target in preventing cancer. In case of breast cancer, curcumin treatment inhibited the proliferation of MCF-7 cells through the inhibition of ERE and the downstream genes of ER including pS2, TGFα, and TGFβ [188].

Conclusions

Despite the fact that a huge number of drugs have been approved for the treatment of diverse cancer types, none of them are effective or devoid of adverse side effects, especially when consumed over a long period of time. In contrast with all of these chemotherapeutic agents, the plant polyphenol curcumin is extremely efficacious and is free from extreme toxicities. It exhibits multifarious pharmacological properties and has the ability to interact with multiple molecular targets and intracellular signaling pathways. However, poor bioavailability limits its therapeutic efficacy and hence demands extensive research to deal with the factors that lead to the weak bioavailability of curcumin. Besides, various analogs of curcumin and different formulations including adjuvants, nanoparticles, liposomes, and so on need to be explored extensively in order to obtain its maximum efficacy, which in turn would facilitate the successful prevention and treatment of cancer. Further, well-controlled and complete clinical trials in higher numbers will be critical in order to take this highly effective and promising agent to the forefront of the therapeutic arsenal in oncology.

We thank Professor P.C. Pradhan from Department of English, Banaras Hindu University, India for carefully reading the article.

Funding

This work was supported by BT/P/SG/ABK/01 awarded to Dr Ajaikumar B. Kunnumakkara by Ministry of Human Resource Development, Government of India.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Abbreviations

     
  • 5-FU

    5-fluorouracil

  •  
  • ACF

    aberrant crypt foci

  •  
  • ALK

    anaplastic lymphoma kinase

  •  
  • ALL

    acute lymphoblastic leukemia

  •  
  • AP-1

    activating protein-1

  •  
  • AQP3

    aquaporin 3

  •  
  • AR

    androgen receptor

  •  
  • Bax

    BCL-2 associated X protein

  •  
  • BCR-ABL

    breakpoint cluster region-Abelson murine leukemia viral oncogene

  •  
  • BPH

    benign prostatic hyperplasia

  •  
  • BRAF

    B-Raf proto oncogene

  •  
  • CD

    cluster of differentiation

  •  
  • CDF

    difluorinated curcumin

  •  
  • CDK4

    cyclin dependent kinase 4

  •  
  • CDK8

    cyclin dependent kinase 8

  •  
  • COX-2

    cyclooxygenase-2

  •  
  • CRC

    colorectal cancer

  •  
  • CXCR4

    CXC chemokine receptor 4

  •  
  • EGCG

    epigallocatechin gallate

  •  
  • EGF

    epidermal growth factor

  •  
  • EGFR

    epidermal growth factor receptor

  •  
  • EGR-1

    early growth response protein-1

  •  
  • eIF2α

    eukaryotic initiation factor 2 alpha

  •  
  • ER

    endrogen receptor

  •  
  • ERE

    estrogen response element

  •  
  • ERK

    extracellular signal-regulated kinase

  •  
  • FGFR

    fibroblast growth factor receptor

  •  
  • FL

    follicular lymphoma

  •  
  • FoXO1

    forkhead box protein O1

  •  
  • HDAC

    histone deacetylase

  •  
  • HER-2

    human epidermal growth factor receptor-2

  •  
  • Hh

    hedgehog

  •  
  • HIF-1

    hypoxia-inducible factor-1

  •  
  • HNSCC

    head and neck squamous cell carcinoma

  •  
  • IKK

    IκB kinase

  •  
  • IKKβ

    inhibitor of nuclear factor κB kinase subunit beta

  •  
  • IL

    interleukin

  •  
  • lncRNA

    long non-coding RNA

  •  
  • JAK2

    janus kinase 2

  •  
  • LPS

    lipopolysaccharide

  •  
  • MAPK

    mitogen activated protein kinase

  •  
  • MMP

    matrix metalloproteinase

  •  
  • MSH

    melanocyte stimulating hormone

  •  
  • MTA1

    metastasis-associated tumor antigen 1

  •  
  • ncRNA

    non-coding RNA

  •  
  • NF-κB

    nuclear factor κB

  •  
  • NHL

    non-Hodgkin's lymphoma

  •  
  • Nrf2

    NF-E2-related factor 2

  •  
  • NSCLC

    non-small cell lung cancer

  •  
  • OSCC

    oral squamous cell carcinoma

  •  
  • PBMC

    peripheral blood mononuclear cell

  •  
  • PDGFR

    platelet derived growth factor receptor

  •  
  • PGE2

    prostaglandin E2

  •  
  • PKCα

    protein kinase C alpha

  •  
  • PSA

    prostate-specific antigen

  •  
  • pSTAT3

    phosphorylated signal transducer and activator of transcription 3

  •  
  • PTCL

    peripheral T-cell lymphoma

  •  
  • PTEN

    phosphatase and tensin homolog

  •  
  • RCC

    renal cell carcinoma

  •  
  • ROS

    reactive oxygen species

  •  
  • SOD

    superoxide dismutase

  •  
  • STAT

    signal transducer and activator of transcription

  •  
  • Tcf-4

    transcription factor- 4

  •  
  • TNF

    tumor necrosis factor

  •  
  • TPA

    12-O-tetradecanoyl phorbol-13-acetate

  •  
  • VEGF

    vascular endothelial growth factor

  •  
  • VEGFR2

    vascular endothelial growth factor receptor 2

  •  
  • WT1

    Wilms’ tumor 1

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