Abstract
Sorafenib, a small inhibitor of tyrosine protein kinases, is currently the standard chemotherapy drug for the treatment of advanced hepatocellular carcinoma (HCC). Although sorafenib improves the survival of HCC patients, its efficacy is not optimal and requires further improvement. Capsaicin, the major active component of chili peppers from the genus Capsicum, is not only the agonist of TRPV1 channel, but also displays antitumor activity and enhances the sensitivity of cancer cells to cytotoxic drugs. In this study, we investigated the antitumor effects of combined sorafenib and capsaicin on HCC cells in vitro and xenograft tumors. Treatment with capsaicin alone dose-dependently inhibited the proliferation of the HCC cell lines PLC/PRF/7, HuH7 and HepG2 with IC50 values of 137, 108 and 140.7 μmol/L, respectively. No obvious expression of TRPV1 channel was detected in the 3 HCC cell lines and TRPV1 channel blockers did not alleviate the cytotoxicity of capsaicin. By contrast, combining capsaicin and sorafenib significantly enhanced the suppression on cell proliferation, achieving a high-level synergistic effect (inhibition rates over 50%) and promoting HCC cell apoptosis. In nude mice with PLC/PRF/5 xenografts, combined administration of capsaicin and sorafenib significantly enhanced the suppression on tumor growth without apparent gross toxicity compared to either agent alone. Mechanistically, capsaicin (10–200 μmol/L) dose-dependently increased the levels of phosphorylated ERK (p-ERK) in PLC/PRF/5 cells, thus leading to enhanced sorafenib sensitivity and a synergistic suppression on the tumor cells. Taken together, our results suggest that capsaicin-increased phosphorylation of ERK contributes to the enhanced antitumor activity of sorafenib, and capsaicin may be useful in improving the efficacy of sorafenib for the treatment of HCC.
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References
Xia J, Song P, Sun Z, Sawakami T, Jia M, Wang Z . Advances of diagnostic and mechanistic studies of gamma-glutamyl transpeptidase in hepatocellular carcinoma. Drug Discov Ther 2016; 10: 181–7.
Sun Z, Zhu Y, Xia J, Sawakami T, Kokudo N, Zhang N . Status of and prospects for cancer vaccines against hepatocellular carcinoma in clinical trials. Biosci Trends 2016; 10: 85–91.
Chen L, Wang L, Diao X, Qian W, Fang L, Pang Y, et al. The diagnostic value of contrast-enhanced ultrasound in differentiating small renal carcinoma and angiomyolipoma. Biosci Trends 2015; 9: 252–8.
Sun H, Song T . Hepatocellular carcinoma: Advances in diagnostic imaging. Drug Discov Ther 2015; 9: 310–8.
Song T . Recent advances in surgical treatment of hepatocellular carcinoma. Drug Discov Ther 2015; 9: 319–30.
Zhang L, Jiang H, Xu G, Chu N, Xu N, Wen H, et al. iTRAQ-based quantitative proteomic analysis reveals potential early diagnostic markers of clear-cell Renal cell carcinoma. Biosci Trends 2016; 10: 210–9.
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356: 125–34.
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378–90.
Ge S, Huang D . Systemic therapies for hepatocellular carcinoma. Drug Discov Ther 2015; 9: 352–62.
Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 2006; 66: 11851–8.
Ramos-Torres A, Bort A, Morell C, Rodriguez-Henche N, Diaz-Laviada I . The pepper's natural ingredient capsaicin induces autophagy blockage in prostate cancer cells. Oncotarget 2016; 7: 1569–83.
FDA Approves New Drug Treatment for Long-Term Pain Relief after Shingles Attacks. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm191003.htm (accessed January 20, 2017).
Jang JJ, Cho KJ, Lee YS, Bae JH . Different modifying responses of capsaicin in a wide-spectrum initiation model of F344 rat. J Korean Med Sci 1991; 6: 31–6.
Kaymaz BT, Cetintas VB, Aktan C, Kosova B . MicroRNA-520a-5p displays a therapeutic effect upon chronic myelogenous leukemia cells by targeting STAT3 and enhances the anticarcinogenic role of capsaicin. Tumour Biol 2014; 35: 8733–42.
Jin J, Lin G, Huang H, Xu D, Yu H, Ma X, et al. Capsaicin mediates cell cycle arrest and apoptosis in human colon cancer cells via stabilizing and activating p53. Int J Biol Sci 2014; 10: 285–95.
Moon DO, Kang CH, Kang SH, Choi YH, Hyun JW, Chang WY, et al. Capsaicin sensitizes TRAIL-induced apoptosis through Sp1-mediated DR5 up-regulation: involvement of Ca2+ influx. Toxicol Appl Pharmacol 2012; 259: 87–95.
Jung MY, Kang HJ, Moon A . Capsaicin-induced apoptosis in SK-Hep-1 hepatocarcinoma cells involves Bcl-2 downregulation and caspase-3 activation. Cancer Lett 2001; 165: 139–45.
Weber LV, Al-Refae K, Wolk G, Bonatz G, Altmuller J, Becker C, et al. Expression and functionality of TRPV1 in breast cancer cells. Breast Cancer (Dove Med Press) 2016; 8: 243–52.
Granato M, Gilardini Montani MS, Filardi M, Faggioni A, Cirone M . Capsaicin triggers immunogenic PEL cell death, stimulates DCs and reverts PEL-induced immune suppression. Oncotarget 2015; 6: 29543–54.
Sanchez AM, Malagarie-Cazenave S, Olea N, Vara D, Chiloeches A, Diaz-Laviada I . Apoptosis induced by capsaicin in prostate PC-3 cells involves ceramide accumulation, neutral sphingomyelinase, and JNK activation. Apoptosis 2007; 12: 2013–24.
Bhutani M, Pathak AK, Nair AS, Kunnumakkara AB, Guha S, Sethi G, et al. Capsaicin is a novel blocker of constitutive and interleukin-6-inducible STAT3 activation. Clin Cancer Res 2007; 13: 3024–32.
Zhang Z, Zhou X, Shen H, Wang D, Wang Y . Phosphorylated ERK is a potential predictor of sensitivity to sorafenib when treating hepatocellular carcinoma: evidence from an in vitro study. BMC Med 2009; 7: 41.
Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006; 24: 4293–300.
Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004; 64: 7099–109.
Wei NN, Lv HN, Wu Y, Yang SL, Sun XY, Lai R, et al. Selective activation of nociceptor TRPV1 channel and reversal of inflammatory pain in mice by a novel coumarin derivative muralatin l from Murraya alata. J Biol Chem 2016; 291: 640–51.
Tai WT, Cheng AL, Shiau CW, Huang HP, Huang JW, Chen PJ, et al. Signal transducer and activator of transcription 3 is a major kinase-independent target of sorafenib in hepatocellular carcinoma. J Hepatol 2011; 55: 1041–8.
Fattori V, Hohmann MS, Rossaneis AC, Pinho-Ribeiro FA, Verri WA . Capsaicin: current understanding of its mechanisms and therapy of pain and other pre-clinical and clinical uses. Molecules 2016; 21: pii: E844.
Yang ZH, Wang XH, Wang HP, Hu LQ, Zheng XM, Li SW . Capsaicin mediates cell death in bladder cancer T24 cells through reactive oxygen species production and mitochondrial depolarization. Urology 2010; 75: 735–41.
Mori A, Lehmann S, O'Kelly J, Kumagai T, Desmond JC, Pervan M, et al. Capsaicin, a component of red peppers, inhibits the growth of androgen-independent, p53 mutant prostate cancer cells. Cancer Res 2006; 66: 3222–9.
Chow J, Norng M, Zhang J, Chai J . TRPV6 mediates capsaicin-induced apoptosis in gastric cancer cells--Mechanisms behind a possible new "hot" cancer treatment. Biochim Biophys Acta 2007; 1773: 565–76.
Lau JK, Brown KC, Dom AM, Witte TR, Thornhill BA, Crabtree CM, et al. Capsaicin induces apoptosis in human small cell lung cancer via the TRPV6 receptor and the calpain pathway. Apoptosis 2014; 19: 1190–201.
Clark R, Lee SH . Anticancer properties of capsaicin against human cancer. Anticancer Res 2016; 36: 837–43.
Irani K, Xia Y, Zweier JL, Sollott SJ, Der CJ, Fearon ER, et al. Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science 1997; 275: 1649–52.
Ramsey MR, Sharpless NE . ROS as a tumour suppressor? Nat Cell Biol 2006; 8: 1213–5.
Renschler MF . The emerging role of reactive oxygen species in cancer therapy. Eur J Cancer 2004; 40: 1934–40.
Jiang X, Feng K, Zhang Y, Li Z, Zhou F, Dou H, et al. Sorafenib and DE605, a novel c-Met inhibitor, synergistically suppress hepatocellular carcinoma. Oncotarget 2015; 6: 12340–56.
Rollyson WD, Stover CA, Brown KC, Perry HE, Stevenson CD, McNees CA, et al. Bioavailability of capsaicin and its implications for drug delivery. J Control Release 2014; 196: 96–105.
Acknowledgements
This project was supported by grants from the National Natural Science Foundation of China (81573410 to KeWei WANG and 81503094 to Jian-jun GAO), the China Postdoctoral Science Foundation (2016 M600524), and the Qingdao Postdoctoral Applied Research Project (2016072; Qingdao University).
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Zhang, Ss., Ni, Yh., Zhao, Cr. et al. Capsaicin enhances the antitumor activity of sorafenib in hepatocellular carcinoma cells and mouse xenograft tumors through increased ERK signaling. Acta Pharmacol Sin 39, 438–448 (2018). https://doi.org/10.1038/aps.2017.156
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DOI: https://doi.org/10.1038/aps.2017.156
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