Cancer & Curcumin
The multifaceted role of curcumin has been demonstrated in various human clinical trials over the past quarter century against many diseases including cancer, cardiovascular disease, diabetes, oral lichen planus, arthritis, and β-thalassemia. In particularly, the anti-cancer potential of curcumin has been successfully exhibited in various types of cancers namely oral, lung, breast, prostate, pancreatic, colorectal, multiple myeloma and head and neck squamous cell carcinoma. With safety and efficacy proven in more than 65 clinical trials and an additional 35 on-going trials (1*), the following figure clearly illustrates the potential role of curcumin in negatively regulating tumor initiation, progression and metastasis.(1*)
...a chemosensitizer and radiosensitizer for tumours
...a chemoprotector and radioprotector for normal organs
Extensive research within the last decade in cell culture and in rodents has revealed that curcumin can sensitize tumors to different chemotherapeutic agents including doxorubicin, 5-FU, paclitaxel, vincristine, melphalan, butyrate, cisplatin, celecoxib, vinorelbine, gemcitabine, oxaliplatin, etoposide, sulfinosine, thalidomide, and bortezomib.
Chemosensitization has been observed in cancers of the breast, colon, pancreas, gastric, liver, blood, lung, prostate, bladder, cervix, ovary, head and neck, and brain and in multiple myeloma, leukemia, and lymphoma.
Similar studies have also revealed that this agent can sensitize a variety of tumors to gamma radiation including glioma, neuroblastoma, cervical carcinoma, epidermal carcinoma, prostate cancer, and colon cancer. How curcumin acts as a chemosensitizer and radiosensitizer has also been studied extensively. Although it acts as a chemosensitizer and radiosensitizer for tumors in some cases, curcumin has also been shown to protect normal organs such as liver, kidney, oral mucosa, and heart from chemotherapy and radiotherapy-induced toxicity.(2*)
Cancer Stem Cells
Over the last decade, there has been a growing body of evidence supporting the concept that tumours are driven by a minor sub-population of self-renewing cancer stem cells (CSCs). Most of the conventional treatment regimens target the non- CSC population of the tumour and fail to eliminate the inherently resistant CSCs (3*). The remaining chemotherapy- resistant CSCs lead to chemotherapy refractory tumour, and may explain the difficulty in complete eradication of cancer and recurrence. Combinatorial therapy of dasatinib and curcumin inhibited cellular growth, invasion and colonosphere formation and also reduced CSC population as evidenced by the decreased expression of CSC- specific markers (4*). Curcumin inhibited signal transducer and activator of transcription-3 (STAT3) phosphorylation, cell viability and tumour sphere formation in colon cancer stem cells (5*). Curcumin also inhibited the side population (SP) of rat C6 glioma cells, characteristic of CSCs (6*). Another report highlighted that curcumin in combination with piperine targets breast CSCs (7*).
TGF-β (transforming growth factor-beta)
TGF-β (transforming growth factor-beta) signaling pathway has the potential to regulate various biological processes including cell growth, differentiation, apoptosis, extracellular matrix modeling, and immune response. TGF-β signaling pathway acts as a tumor suppressor, but alterations in TGF-β signaling pathway promotes cancer cell growth, migration, invasion, angiogenesis, and metastasis.
Curcumin and emodin effectively down regulate TGF-β signaling pathway by decreasing the expression of TGF-β Receptor II, P-Smad3 and Smad4, and also counterbalance the tumorigenic effects of TGF-β by inhibiting the TGF-β- induced migration and invasion in cervical cancer cell(8*).
Another trial showed that curcumin at 10μM can suppress 81.5% of over express TGF-ß expression protein in breast cancer cell (9*). Curcumin inhibited doxorubicin-induced EMT by inhibiting the TGF-β and PI3K/AKT signaling pathways (10*). Curcumin also inhibited nuclear factor-κB pathway and down regulated inflammatory factors including TNF-α, interleukin (IL)-6, IL-8, and TGF-β induced by thoracic irradiation for lung cancer treatment(11*). In lung cancer radiation treatment, radiation-induced transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF) expression, and collagen accumulation were inhibited by curcumin (12*). Curcumin blocks multiple sites of the TGF-beta signaling cascade in kidney cancer cells (Gaedeke J1, Noble NA, Border WA).
The above study clearly shows that curcumin can target cancer stem cell and TGF-ß that conventional treatments do not, and a more effective treatment outcome is possible if curcumin is used in combination with chemo and radiation treatment. For those who have completed their conventional treatment, 2-3 months of curcumin supplementation (High dose, 1.5g ~ 2.5g) is likened to having another course of chemo, by helping to regulate TGF-ß levels, cancer stem cells, reducing the chance of cancer spreading, shrinking the tumors.
(*1)The Multifaceted Role of Curcumin in Cancer Prevention and Treatment. Molecules 2015, 20, 2728-2769; doi:10.3390/molecules20022728 (http://www.mdpi.com/1420-3049/20/2/2728)
(*2) Goel A1, Aggarwal BB, Curcumin, the golden spice from Indian saffron, is a chemosensitizer and radiosensitizer for tumors and chemoprotector and radioprotector for normal organs. Nutr Cancer. 2010;62(7):919-30.
(*3) Dean M, Fojo T and Bates S: Tumour stem cells and drug resistance. Nat Rev Cancer 5: 275-284, 2005.
(*4) Nautiyal J, Kanwar SS, Yu Y and Majumdar AP: Combination of dasatinib and curcumin eliminates chemoresistant colon cancer cells. J Mol Signal 6: 7, 2011.
(*5) Lin L, Fuchs J, Li C, Olson V, Bekaii-Saab T and Lin J: STAT3 signaling pathway is necessary for cell survival and tumorsphere forming capacity in ALDH/CD133 stem cell-like human colon cancer cells. Biochem Biophys Res Commun 416: 246-251, 2011.
(*6) Fong D, Yeh A, Naftalovich R, Choi TH and Chan MM: Curcumin inhibits the side population (SP) phenotype of the rat C6 glioma cell line: towards targeting of cancer stem cells with phytochemicals. Cancer Lett 293: 65-72, 2010.
(*7) Kakarala M, Brenner DE, Korkaya H, Cheng C, Tazi K, Ginestier C, Liu S, Dontu G and Wicha MS: Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat 122: 777-785, 2010.
(*8) Pooja Chandrakant Thacker, Devarajan Karunagaran, Signaling Pathway in Human Cervical Cancer Cells. PLoS ONE 10(3): e0120045, doi:10.1371/journal.pone.0120045
(*9) Curcumin inhibited TGF-β1-stimulated MMP-9 and the invasive phenotype in MDA-MB-231 cells. Cells. Asian Pacific J Cancer Prev, 13 (11), 5709-5714.
(*10) Curcumin suppresses doxorubicin-induced epithelial-mesenchymal transition via the inhibition of TGF-β and PI3K/AKT signaling pathways in triple-negative breast cancer cells. J Agric Food Chem. 2013 Dec 4;61(48):11817-24.
(*11) A systemic administration of liposomal curcumin inhibits radiation pneumonitis and sensitizes lung carcinoma to radiation. Int J Nanomedicine. 2012;7:2601-11.
(*12) Curcumin Attenuates Radiation-Induced Inflammation and Fibrosis in Rat Lungs. Korean J Physiol Pharmacol. 2013 August; 17(4): 267–274.
Some Examples On Chemo/Radiation Sensitizer Studies
Combined Treatment With Nano Curcumin And Gemcitabine On Pancreatic Cancer
Systemic Administration Of Polymeric - Encapsulated Nanoparticle Curcumin (Nanocurc™) [or PEN-Cur analogue type] Blocks Tumor Growth And Metastases In Preclinical Models Of Pancreatic Cancer
A & B : NanoCurc [or PEN-Cur type] or Gemcitabine individually can help prevent cancer spreading
to the lungs and peritoneum, and reduce the spread to lymph nodes by 80%.
C : NanoCurc [or PEN-Cur type] and Gemcitabine in combination can help prevent cancer spreading to
these 3 organs.
In 2012, Johns Hopkins cancer research center's clinical trial of adding [PEN-Cur type] Nano-curcumin to Nano Daxorubicine onto resistant prostate, multiple myeloma, ovarian and acute leukemia
tumour as a treatment showed that - [PEN-Cur type] Nano-curcumin (in yellow) reduced cancer tumour size much more than DOX (in red), and, as a combined treatment (in orange) reduced the tumour
size to more than 90% in 23 days.
Lower Breast Cancer Metastases To Lung
Figure 1. Curcumin, Taxol, and the combination of both inhibit breast cancer metastasis to the lungs in mice. Inhibition of metastasis was statistically significant for both
Curcumin and Taxol vs. control; inhibition of metastasis was also significantly greater for Curcumin + Taxol vs. Taxol alone. Adapted from Aggarwal et al, 2005.
SKl-ll Ovarian Cancer Cells
A : Untreated ovarian cancer cells.
B : Nano curcumin [PEN-Cur type] alone kills 25% of cancer cells.
C : SKl-ll alone kills 40% of cancer
D : A combination of Nano curcumin [PEN-Cur equivalent] & SKl-ll kills 80% of cancer cells.
Curcumin Increased Radiation Respond Rate On Ovarian Cancer Cells