Capsaicin induces apoptosis and autophagy in human melanoma cells

Chu,Haihan; Li,Meng; Wang,Xiuchun

doi:10.3892/ol.2019.10206

Capsaicin induces apoptosis and autophagy in human melanoma cells

Authors:
- Haihan Chu
- Meng Li
- Xiuchun Wang
View Affiliations

Affiliations: Department of Burn and Plastic Surgery, Jining First People's Hospital, Jining, Shandong 272011, P.R. China
Published online on: April 3, 2019 https://doi.org/10.3892/ol.2019.10206
Pages: 4827-4834
Copyright: © Chu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Melanoma is the most lethal type of skin cancer; rapid metastasis and resistance to conventional radio‑ and chemotherapy make melanoma the most aggressive type of skin cancer. In addition, there is a high recurrence rate within 1 year among patients with melanoma following traditional treatment by chemotherapy or immunotherapy, and these treatment options are only useful in advanced stages. As the efficiency of treatment options for melanoma is not ideal, the present study aimed to confirm that capsaicin has inhibitory effects on the human melanoma A375 and C8161 cell lines in vitro. Capsaicin, the active component of peppers, has been reported to possess substantial anticarcinogenic and antimutagenic activities. Additionally, capsaicin exhibits an inhibitory effect on tumor growth in numerous malignant cell lines. In the present study, flow cytometry, fluorescent puncta detection and western blotting were performed. The experimental results indicated that capsaicin activated apoptosis, and that apoptosis induction was associated with poly(ADP‑ribose) polymerase (PARP) cleavage and activation of caspase‑3. Additionally, the formation of autophagosomes and accumulation of microtubule‑associated proteins 1A/1B light chain 3B‑II and beclin 1 suggested that capsaicin induced autophagy in human melanoma cells. Furthermore, inhibiting capsaicin‑induced autophagy promoted the activation of cleaved caspase‑3 and PARP proteins, which are associated with apoptosis. In addition, inhibition of autophagy using 3‑MA enhanced capsaicin‑induced cell death, indicating that capsaicin‑induced autophagy is a pro‑survival process in cells. In conclusion, the results of the present study revealed that capsaicin induced cell apoptosis and autophagy in human melanoma cells and capsaicin may be considered as a novel candidate drug for melanoma treatment.

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1	Schadendorf D, Fisher DE, Garbe C, Gershenwald JE, Grob JJ, Halpern A, Herlyn M, Marchetti MA, McArthur G, Ribas A, et al: Melanoma. Nat Rev Dis Primers. 1:150032015. View Article : Google Scholar : PubMed/NCBI
2	Leiter U and Garbe C: Epidemiology of melanoma and nonmelanoma skin cancer-the role of sunlight. Adv Exp Med Biol. 624:89–103. 2008. View Article : Google Scholar : PubMed/NCBI
3	Wei W, Ehlerding EB, Lan X, Luo Q and Cai W: PET and SPECT imaging of melanoma: The state of the art. Eur J Nucl Med Mol Imaging. 45:132–150. 2018. View Article : Google Scholar : PubMed/NCBI
4	Schadendorf D and Hauschild A: Melanoma in 2013: Melanoma-the run of success continues. Nat Rev Clin Oncol. 11:75–76. 2014. View Article : Google Scholar : PubMed/NCBI
5	Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, Buzaid AC, Cochran AJ, Coit DG, Ding S, et al: Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 27:6199–6206. 2009. View Article : Google Scholar : PubMed/NCBI
6	Srinivasan K: Biological activities of red pepper (Capsicum annuum) and its pungent principle capsaicin: A review. Crit Rev Food Sci Nutr. 56:1488–1500. 2016. View Article : Google Scholar : PubMed/NCBI
7	Ludy MJ, Moore GE and Mattes RD: The effects of capsaicin and capsiate on energy balance: Critical review and meta-analyses of studies in humans. Chem Senses. 37:103–121. 2012. View Article : Google Scholar : PubMed/NCBI
8	Patel S, Trueman D, Bentley A, Poole C and Chambers C: Cost-effectiveness of capsaicin 8% patch (Qutenza(tm)) compared with pregabalin for the treatment of patients with peripheral neuropathic pain (Pnp) in Scotland. Value Health. 17:A5312014. View Article : Google Scholar : PubMed/NCBI
9	Fattori V, Hohmann MS, Rossaneis AC, Pinho-Ribeiro FA and Verri WA: Capsaicin: Current understanding of its mechanisms and therapy of pain and other pre-clinical and clinical uses. Molecules. 21(pii): E8442016. View Article : Google Scholar : PubMed/NCBI
10	Bernstein JA, Davis BP, Picard JK, Cooper JP, Zheng S and Levin LS: A randomized, double-blind, parallel trial comparing capsaicin nasal spray with placebo in subjects with a significant component of nonallergic rhinitis. Ann Allergy Asthma Immunol. 107:171–178. 2011. View Article : Google Scholar : PubMed/NCBI
11	Díaz-Laviada I and Rodríguez-Henche N: The potential antitumor effects of capsaicin. Prog Drug Res. 68:181–208. 2014.PubMed/NCBI
12	Ramos-Torres Á, Bort A, Morell C, Rodríguez-Henche N and Díaz-Laviada I: The pepper's natural ingredient capsaicin induces autophagy blockage in prostate cancer cells. Oncotarget. 7:1569–1583. 2016. View Article : Google Scholar : PubMed/NCBI
13	Lin YT, Wang HC, Hsu YC, Cho CL, Yang MY and Chien CY: Capsaicin induces autophagy and apoptosis in human nasopharyngeal carcinoma cells by downregulating the PI3K/AKT/mTOR pathway. Int J Mol Sci. 18(pii): E13432017. View Article : Google Scholar : PubMed/NCBI
14	Yang KM, Pyo JO, Kim GY, Yu R, Han IS, Ju SA, Kim WH and Kim BS: Capsaicin induces apoptosis by generating reactive oxygen species and disrupting mitochondrial transmembrane potential in human colon cancer cell lines. Cell Mol Biol Lett. 14:497–510. 2009. View Article : Google Scholar : PubMed/NCBI
15	Zhang R, Xia Y, Wang Z, Zheng J, Chen Y, Li X, Wang Y and Ming H: Serum long non coding RNA MALAT-1 protected by exosomes is up-regulated and promotes cell proliferation and migration in non-small cell lung cancer. Biochem Biophys Res Commun. 490:406–414. 2017. View Article : Google Scholar : PubMed/NCBI
16	Huang SP, Chen JC, Wu CC, Chen CT, Tang NY, Ho YT, Lo C, Lin JP, Chung JG and Lin JG: Capsaicin-induced apoptosis in human hepatoma HepG2 cells. Anticancer Res. 29:165–174. 2009.PubMed/NCBI
17	Ouyang L, Shi Z, Zhao S, Wang FT, Zhou TT, Liu B and Bao JK: Programmed cell death pathways in cancer: A review of apoptosis, autophagy and programmed necrosis. Cell Prolif. 45:487–498. 2012. View Article : Google Scholar : PubMed/NCBI
18	Jun HS, Park T, Lee CK, Kang MK, Park MS, Kang HI, Surh YJ and Kim OH: Capsaicin induced apoptosis of B16-F10 melanoma cells through down-regulation of Bcl-2. Food Chem Toxicol. 45:708–715. 2007. View Article : Google Scholar : PubMed/NCBI
19	Eisenberg-Lerner A and Kimchi A: The paradox of autophagy and its implication in cancer etiology and therapy. Apoptosis. 14:376–391. 2009. View Article : Google Scholar : PubMed/NCBI
20	Yang ZJ, Chee CE, Huang S and Sinicrope FA: The role of autophagy in cancer: Therapeutic implications. Mol Cancer Ther. 10:1533–1541. 2011. View Article : Google Scholar : PubMed/NCBI
21	Maiuri MC, Zalckvar E, Kimchi A and Kroemer G: Self-eating and self-killing: Crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 8:741–752. 2007. View Article : Google Scholar : PubMed/NCBI
22	Lo JA and Fisher DE: The melanoma revolution: From UV carcinogenesis to a new era in therapeutics. Science. 346:945–949. 2014. View Article : Google Scholar : PubMed/NCBI
23	Lin JY and Fisher DE: Melanocyte biology and skin pigmentation. Nature. 445:843–850. 2007. View Article : Google Scholar : PubMed/NCBI
24	Dong J, Phelps RG, Qiao R, Yao S, Benard O, Ronai Z and Aaronson SA: BRAF oncogenic mutations correlate with progression rather than initiation of human melanoma. Cancer Res. 63:3883–3885. 2003.PubMed/NCBI
25	Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O'Dwyer PJ, Lee RJ, Grippo JF, Nolop K and Chapman PB: Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 363:809–819. 2010. View Article : Google Scholar : PubMed/NCBI
26	Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, et al: Dabrafenib in BRAF-mutated metastatic melanoma: A multicentre, open-label, phase 3 randomised controlled trial. Lancet. 380:358–365. 2012. View Article : Google Scholar : PubMed/NCBI
27	Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, et al: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 364:2507–2516. 2011. View Article : Google Scholar : PubMed/NCBI
28	Ribas A, Gonzalez R, Pavlick A, Hamid O, Gajewski TF, Daud A, Flaherty L, Logan T, Chmielowski B, Lewis K, et al: Combination of vemurafenib and cobimetinib in patients with advanced BRAF (V600)-mutated melanoma: A phase 1b study. Lancet Oncol. 15:954–965. 2014. View Article : Google Scholar : PubMed/NCBI
29	Dvořánková B, Szabo P, Kodet O, Strnad H, Kolář M, Lacina L, Krejčí E, Naňka O, Šedo A and Smetana K Jr: Intercellular crosstalk in human malignant melanoma. Protoplasma. 254:1143–1150. 2017. View Article : Google Scholar : PubMed/NCBI
30	Toh CC, Lee TS and Kiang AK: The pharmacological actions of capsaicin and analogues. Br J Pharmacol Chemother. 10:175–182. 1955. View Article : Google Scholar : PubMed/NCBI
31	Sekine R, Satoh T, Takaoka A, Saeki K and Yokozeki H: Anti pruritic effects of topical crotamiton, capsaicin, and a corticosteroid on pruritogen-induced scratching behavior. Exp Dermatol. 21:201–204. 2012. View Article : Google Scholar : PubMed/NCBI
32	Liao HT, Lee HJ, Ho YC and Chiou LC: Capsaicin in the periaqueductal gray induces analgesia via metabotropic glutamate receptor-mediated endocannabinoid retrograde disinhibition. Br J Pharmacol. 163:330–345. 2011. View Article : Google Scholar : PubMed/NCBI
33	Clark R and Lee SH: Anticancer properties of capsaicin against human cancer. Anticancer Res. 36:837–843. 2016.PubMed/NCBI
34	Chapa-Oliver AM and Mejía-Teniente L: Capsaicin: From plants to a cancer-suppressing agent. Molecules. 21(pii): E9312016. View Article : Google Scholar : PubMed/NCBI
35	Shin DH, Kim OH, Jun HS and Kang MK: Inhibitory effect of capsaicin on B16-F10 melanoma cell migration via the phosphatidylinositol 3-kinase/Akt/Rac1 signal pathway. Exp Mol Med. 40:486–494. 2008. View Article : Google Scholar : PubMed/NCBI
36	Lin CH, Lu WC, Wang CW, Chan YC and Chen MK: Capsaicin induces cell cycle arrest and apoptosis in human KB cancer cells. BMC Complement Altern Med. 13:462013. View Article : Google Scholar : PubMed/NCBI
37	Liu Z, Ouyang L, Peng H and Zhang WZ: Oridonin: Targeting programmed cell death pathways as an anti-tumour agent. Cell Prolif. 45:499–507. 2012. View Article : Google Scholar : PubMed/NCBI
38	Hail N Jr, Carter BZ, Konopleva M and Andreeff M: Apoptosis effector mechanisms: A requiem performed in different keys. Apoptosis. 11:889–904. 2006. View Article : Google Scholar : PubMed/NCBI
39	Mukhopadhyay S, Panda PK, Sinha N, Das DN and Bhutia SK: Autophagy and apoptosis: Where do they meet? Apoptosis. 19:555–566. 2014. View Article : Google Scholar : PubMed/NCBI
40	Boulares AH, Yakovlev AG, Ivanova V, Stoica BA, Wang G, Iyer S and Smulson M: Role of poly(ADP-ribose) polymerase (PARP) cleavage in apoptosis. Caspase 3-resistant PARP mutant increases rates of apoptosis in transfected cells. J Biol Chem. 274:22932–22940. 1999. View Article : Google Scholar : PubMed/NCBI
41	Kulms D and Schwarz T: Molecular mechanisms of UV-induced apoptosis. Photodermatol Photoimmunol Photomed. 16:195–201. 2000. View Article : Google Scholar : PubMed/NCBI
42	Liu YP, Dong FX, Chai X, Zhu S, Zhang BL and Gao DS: Role of autophagy in capsaicin-induced apoptosis in U251 glioma cells. Cell Mol Neurobiol. 36:737–743. 2016. View Article : Google Scholar : PubMed/NCBI
43	Radogna F, Dicato M and Diederich M: Cancer-type-specific crosstalk between autophagy, necroptosis and apoptosis as a pharmacological target. Biochem Pharmacol. 94:1–11. 2015. View Article : Google Scholar : PubMed/NCBI
44	Li M, Tan J, Miao Y, Lei P and Zhang Q: The dual role of autophagy under hypoxia-involvement of interaction between autophagy and apoptosis. Apoptosis. 20:769–777. 2015. View Article : Google Scholar : PubMed/NCBI
45	Fu D, Yu JY, Yang S, Wu M, Hammad SM, Connell AR, Du M, Chen J and Lyons TJ: Survival or death: A dual role for autophagy in stress-induced pericyte loss in diabetic retinopathy. Diabetologia. 59:2251–2261. 2016. View Article : Google Scholar : PubMed/NCBI
46	Ravegnini G, Sammarini G, Nannini M, Pantaleo MA, Biasco G, Hrelia P and Angelini S: Gastrointestinal stromal tumors (GIST): Facing cell death between autophagy and apoptosis. Autophagy. 13:452–463. 2017. View Article : Google Scholar : PubMed/NCBI