Interferon-β sensitizes human malignant melanoma cells to temozolomide-induced apoptosis and autophagy

Kotaro Makita, Hiroyuki Hara, Emiko Sano, Yutaka Okamoto, Yushi Ochiai, Tomonori Harada, Takuya Ueda, Tomohiro Nakayama, Shin Aizawa, Atsuo Yoshino

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Abstract

Malignant melanoma is a highly aggressive skin cancer that is highly resistant to chemotherapy. Adjuvant therapy is administered to patients with melanoma that possess no microscopic metastases or have a high risk of developing microscopic metastases. Methylating agents, including dacarbazine (DTIC) and temozolomide (TMZ), pegylated interferon (IFN)-α2b and interleukin-2 have been approved for adjuvant immuno-chemotherapy; however, unsatisfactory results have been reported following the administration of methylating agents. IFN-β has been considered to be a signaling molecule with an important therapeutic potential in cancer. The aim of the present study was to elucidate whether antitumor effects could be augmented by the combination of TMZ and IFN-β in malignant melanoma. We evaluated the efficacy of TMZ and IFN-β by comparing O 6 -methylguanine-DNA transferase (MGMT)-proficient and -deficient cells, as MGMT has been reported to be associated with the resistance to methylating agents. Cell viability was determined by counting living cells with a Coulter counter, and apoptosis was analyzed by dual staining with Annexin V Alexa FluorR 488 and propidium iodide. The expression of proteins involved in the cell cycle, apoptosis and autophagy was evaluated by western blot analysis. The combined treatment with TMZ and IFN-β suppressed cell proliferation and induced cell cycle arrest. We also demonstrated that a combination of TMZ and IFN-β enhanced apoptosis and autophagy more efficiently compared with TMZ treatment alone. These findings suggest that antitumor activity may be potentiated by IFN-β in combination with TMZ.

Original languageEnglish
Pages (from-to)1864-1874
Number of pages11
JournalInternational journal of oncology
Volume54
Issue number5
DOIs
Publication statusPublished - 2019 Apr
Externally publishedYes

Keywords

  • Apoptosis
  • Autophagy
  • Human interferon-β
  • MGMT
  • Malignant melanoma
  • Temozolomide

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Makita, K., Hara, H., Sano, E., Okamoto, Y., Ochiai, Y., Harada, T., Ueda, T., Nakayama, T., Aizawa, S., & Yoshino, A. (2019). Interferon-β sensitizes human malignant melanoma cells to temozolomide-induced apoptosis and autophagy. International journal of oncology, 54(5), 1864-1874. https://doi.org/10.3892/ijo.2019.4743