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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.

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