title: Diphenhydramine induces melanoma cell apoptosis by suppressing STAT3/MCL-1 survival signaling and retards B16-F10 melanoma growth in vivo.
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.
authors: Department of Life Science, National Chung Hsing University, Taichung 40227, Taiwan, R.O.C.
authors: Chi-Hung R
authors: CR
authors: Or
authors: Department of Life Science, National Chung Hsing University, Taichung 40227, Taiwan, R.O.C.
authors: Hong-Lin
authors: HL
authors: Su
authors: Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan, R.O.C.
authors: Wee-Chyan
authors: WC
authors: Lee
authors: Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan, R.O.C.
authors: Shu-Yi
authors: SY
authors: Yang
authors: Department of Anesthesiology, Kuang Tien General Hospital, Dajia Branch, Taichung 43761, Taiwan, R.O.C.
authors: Cheesang
authors: C
authors: Ho
authors: Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan, R.O.C.
authors: Chia-Che
authors: CC
authors: Chang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002470:Cell Survival / Q000187:drug effects; D004155:Diphenhydramine / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008544:Melanocytes / Q000187:drug effects / Q000502:physiology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D008810:Mice, Inbred C57BL; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D009368:Neoplasm Transplantation; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D004155:Diphenhydramine