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
  • View Affiliations

  • 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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December-2016
Volume 36 Issue 6

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Or CR, Su H, Lee W, Yang S, Ho C and Chang C: Diphenhydramine induces melanoma cell apoptosis by suppressing STAT3/MCL-1 survival signaling and retards B16-F10 melanoma growth in vivo. Oncol Rep 36: 3465-3471, 2016.
APA
Or, C.R., Su, H., Lee, W., Yang, S., Ho, C., & Chang, C. (2016). Diphenhydramine induces melanoma cell apoptosis by suppressing STAT3/MCL-1 survival signaling and retards B16-F10 melanoma growth in vivo. Oncology Reports, 36, 3465-3471. https://doi.org/10.3892/or.2016.5201
MLA
Or, C. R., Su, H., Lee, W., Yang, S., Ho, C., Chang, C."Diphenhydramine induces melanoma cell apoptosis by suppressing STAT3/MCL-1 survival signaling and retards B16-F10 melanoma growth in vivo". Oncology Reports 36.6 (2016): 3465-3471.
Chicago
Or, C. R., Su, H., Lee, W., Yang, S., Ho, C., Chang, C."Diphenhydramine induces melanoma cell apoptosis by suppressing STAT3/MCL-1 survival signaling and retards B16-F10 melanoma growth in vivo". Oncology Reports 36, no. 6 (2016): 3465-3471. https://doi.org/10.3892/or.2016.5201