Diphenhydramine induces melanoma cell apoptosis by suppressing STAT3/MCL-1 survival signaling and retards B16-F10 melanoma growth in vivo

Or,Chi-Hung R.; Su,Hong-Lin; Lee,Wee-Chyan; Yang,Shu-Yi; Ho,Cheesang; Chang,Chia-Che

doi:10.3892/or.2016.5201

Diphenhydramine induces melanoma cell apoptosis by suppressing STAT3/MCL-1 survival signaling and retards B16-F10 melanoma growth in vivo

Authors:
- Chi-Hung R. Or
- Hong-Lin Su
- Wee-Chyan Lee
- Shu-Yi Yang
- Cheesang Ho
- Chia-Che Chang
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Affiliations: Department of Life Science, National Chung Hsing University, Taichung 40227, Taiwan, R.O.C., Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan, R.O.C., Department of Anesthesiology, Kuang Tien General Hospital, Dajia Branch, Taichung 43761, Taiwan, R.O.C.
Published online on: October 25, 2016 https://doi.org/10.3892/or.2016.5201
Pages: 3465-3471

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Abstract

Melanoma is the most aggressive skin malignancy with a high rate of mortality and is frequently refractory to many therapeutics, thus demanding the discovery of novel effective anti-melanoma agents. Diphenhydramine (DPH) is an H1 histamine receptor antagonist and a relatively safe drug. Previous studies have revealed the in vitro cytotoxicity of DPH against melanoma cells, but the mechanisms involved concerning its cytotoxicity and the in vivo anti-melanoma effect remain unknown. We herein present the first evidence supporting that DPH is selectively proapoptotic for a panel of melanoma cell lines irrespective of BRAFV600E status while sparing normal melanocytes. Of note, DPH effectively suppressed tumor growth and prolonged the length of survival of mice bearing B16-F10 melanoma. Mechanistic investigation further revealed that DPH downregulated antiapoptotic MCL-1, whereas MCL-1 overexpression impeded the proapoptotic action of DPH. Moreover, DPH attenuated STAT3 activation, as evidenced by the reduced levels of tyrosine 705-phosphorylated STAT3. Notably, ectopic expression of constitutively active STAT3 mutant reduced DPH-induced apoptosis but also protected MCL-1 from downregulation by DPH, illustrating that DPH impairs STAT3 activation to block STAT3-mediated induction of MCL-1 in eliciting apoptosis. Collectively, we for the first time validate the in vivo anti‑melanoma effect of DPH and also establish DPH as a drug targeting STAT3/MCL-1 survival signaling pathway to induce apoptosis. Our discovery therefore suggests the potential to repurpose DPH as an anti-melanoma therapeutic agent.

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1	Friedman RJ and Heilman ER: The pathology of malignant melanoma. Dermatol Clin. 20:659–676. 2002. View Article : Google Scholar : PubMed/NCBI
2	Lens MB and Dawes M: Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma. Br J Dermatol. 150:179–185. 2004. View Article : Google Scholar : PubMed/NCBI
3	Houghton AN and Polsky D: Focus on melanoma. Cancer Cell. 2:275–278. 2002. View Article : Google Scholar : PubMed/NCBI
4	Diepgen TL and Mahler V: The epidemiology of skin cancer. Br J Dermatol. 146:(Suppl 61). 1–6. 2002. View Article : Google Scholar : PubMed/NCBI
5	Linos E, Swetter SM, Cockburn MG, Colditz GA and Clarke CA: Increasing burden of melanoma in the United States. J Invest Dermatol. 129:1666–1674. 2009. View Article : Google Scholar : PubMed/NCBI
6	Antihistamine Drugs, . Drug information. 85. American Society of Hospital Pharmacists; Bethesda, MD: 1985
7	Dupuis LL and Nathan PC: Optimizing emetic control in children receiving antineoplastic therapy: Beyond the guidelines. Paediatr Drugs. 12:51–61. 2010. View Article : Google Scholar : PubMed/NCBI
8	Kuo CC, Huang RC and Lou BS: Inhibition of Na⁺ current by diphenhydramine and other diphenyl compounds: Molecular determinants of selective binding to the inactivated channels. Mol Pharmacol. 57:135–143. 2000.PubMed/NCBI
9	Green SM, Rothrock SG and Gorchynski J: Validation of diphenhydramine as a dermal local anesthetic. Ann Emerg Med. 23:1284–1289. 1994. View Article : Google Scholar : PubMed/NCBI
10	Jangi SM, Díaz-Pérez JL, Ochoa-Lizarralde B, Martín-Ruiz I, Asumendi A, Pérez-Yarza G, Gardeazabal J, Díaz-Ramón JL and Boyano MD: H1 histamine receptor antagonists induce genotoxic and caspase-2-dependent apoptosis in human melanoma cells. Carcinogenesis. 27:1787–1796. 2006. View Article : Google Scholar : PubMed/NCBI
11	Hsieh HY, Shieh JJ, Chen CJ, Pan MY, Yang SY, Lin SC, Chang JS, Lee AYL and Chang CC: Prodigiosin down-regulates SKP2 to induce p27^KIP1 stabilization and antiproliferation in human lung adenocarcinoma cells. Br J Pharmacol. 166:2095–2108. 2012. View Article : Google Scholar : PubMed/NCBI
12	Zhuang L, Lee CS, Scolyer RA, McCarthy SW, Zhang XD, Thompson JF and Hersey P: Mcl-1, Bcl-XL and Stat3 expression are associated with progression of melanoma whereas Bcl-2, AP-2 and MITF levels decrease during progression of melanoma. Mod Pathol. 20:416–426. 2007. View Article : Google Scholar : PubMed/NCBI
13	Perciavalle RM and Opferman JT: Delving deeper: MCL-1s contributions to normal and cancer biology. Trends Cell Biol. 23:22–29. 2013. View Article : Google Scholar : PubMed/NCBI
14	Belmar J and Fesik SW: Small molecule Mcl-1 inhibitors for the treatment of cancer. Pharmacol Ther. 145:76–84. 2015. View Article : Google Scholar : PubMed/NCBI
15	Becker TM, Boyd SC, Mijatov B, Gowrishankar K, Snoyman S, Pupo GM, Scolyer RA, Mann GJ, Kefford RF, Zhang XD, et al: Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor. Oncogene. 33:1158–1166. 2014. View Article : Google Scholar : PubMed/NCBI
16	Niu G, Bowman T, Huang M, Shivers S, Reintgen D, Daud A, Chang A, Kraker A, Jove R and Yu H: Roles of activated Src and Stat3 signaling in melanoma tumor cell growth. Oncogene. 21:7001–7010. 2002. View Article : Google Scholar : PubMed/NCBI
17	Siveen KS, Sikka S, Surana R, Dai X, Zhang J, Kumar AP, Tan BKH, Sethi G and Bishayee A: Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors. Biochim Biophys Acta. 1845:136–154. 2014.PubMed/NCBI
18	Zhao C, Li H, Lin HJ, Yang S, Lin J and Liang G: Feedback activation of STAT3 as a cancer drug-resistance mechanism. Trends Pharmacol Sci. 37:47–61. 2016. View Article : Google Scholar : PubMed/NCBI
19	Mukherjee N, Lu Y, Almeida A, Lambert K, Shiau CW, Su JC, Luo Y, Fujita M, Robinson WA, Robinson SE, et al: Use of a MCL-1 inhibitor alone to de-bulk melanoma and in combination to kill melanoma initiating cells. Oncotarget. Apr 12–2016.(Epub ahead of print).
20	Jangi SM, Asumendi A, Arlucea J, Nieto N, Perez-Yarza G, Morales MC, de la Fuente-Pinedo M and Boyano MD: Apoptosis of human T-cell acute lymphoblastic leukemia cells by diphenhydramine, an H1 histamine receptor antagonist. Oncol Res. 14:363–372. 2004.PubMed/NCBI
21	Jangi SM, Ruiz-Larrea MB, Nicolau-Galmés F, Andollo Y, Arroyo-Berdugo N, Ortega-Martínez I, Díaz-Pérez JL and Boyano MD: Terfenadine-induced apoptosis in human melanoma cells is mediated through Ca⁺² homeostasis modulation and tyrosine kinase activity, independently of H1 histamine receptors. Carcinogenesis. 29:500–509. 2008. View Article : Google Scholar : PubMed/NCBI
22	García-Quiroz J and Camacho J: Astemizole: An old anti- histamine as a new promising anti-cancer drug. Anticancer Agents Med Chem. 11:307–314. 2011. View Article : Google Scholar : PubMed/NCBI
23	Roger S, Gillet L, Le Guennec JY and Besson P: Voltage-gated sodium channels and cancer: Is excitability their primary role? Front Pharmacol. 6:1522015. View Article : Google Scholar : PubMed/NCBI
24	Fofaria NM, Frederick DT, Sullivan RJ, Flaherty KT and Srivastava SK: Overexpression of Mcl-1 confers resistance to BRAF^V600E inhibitors alone and in combination with MEK1/2 inhibitors in melanoma. Oncotarget. 6:40535–40556. 2015.PubMed/NCBI
25	Liu F, Cao J, Wu J, Sullivan K, Shen J, Ryu B, Xu Z, Wei W and Cui R: Stat3-targeted therapies overcome the acquired resistance to vemurafenib in melanomas. J Invest Dermatol. 133:2041–2049. 2013. View Article : Google Scholar : PubMed/NCBI