Physachenolide C induces complete regression of established murine melanoma tumors via apoptosis and cell cycle arrest
AffiliationDepartment of Pediatrics, University of Arizona
Banner University Medical Center, University of Arizona
Banner Children's at Desert, University of Arizona
Department of Immunobiology, University of Arizona
Department of Medicine, University of Arizona
Department of Pathology, University of Arizona
The University of Arizona Cancer Center
MetadataShow full item record
PublisherNeoplasia Press, Inc.
CitationAdams, A. C., Macy, A. M., Kang, P., Castro-Ochoa, K. F., Wijeratne, E. M. K., Xu, Y.-M., Liu, M. X., Charos, A., Bosenberg, M. W., Gunatilaka, A. A. L., Sertil, A. R., & Hastings, K. T. (2022). Physachenolide C induces complete regression of established murine melanoma tumors via apoptosis and cell cycle arrest. Translational Oncology.
RightsCopyright © 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.
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AbstractMelanoma is an aggressive skin cancer that metastasizes to other organs. While immune checkpoint blockade with anti-PD-1 has transformed the treatment of advanced melanoma, many melanoma patients fail to respond to anti-PD-1 therapy or develop acquired resistance. Thus, effective treatment of melanoma still represents an unmet clinical need. Our prior studies support the anti-cancer activity of the 17β-hydroxywithanolide class of natural products, including physachenolide C (PCC). As single agents, PCC and its semi-synthetic analog demonstrated direct cytotoxicity in a panel of murine melanoma cell lines, which share common driver mutations with human melanoma; the IC50 values ranged from 0.19–1.8 µM. PCC treatment induced apoptosis of tumor cells both in vitro and in vivo. In vivo treatment with PCC alone caused the complete regression of established melanoma tumors in all mice, with a durable response in 33% of mice after discontinuation of treatment. T cell-mediated immunity did not contribute to the therapeutic efficacy of PCC or prevent tumor recurrence in YUMM2.1 melanoma model. In addition to apoptosis, PCC treatment induced G0-G1 cell cycle arrest of melanoma cells, which upon removal of PCC, re-entered the cell cycle. PCC-induced cycle cell arrest likely contributed to the in vivo tumor recurrence in a portion of mice after discontinuation of treatment. Thus, 17β-hydroxywithanolides have the potential to improve the therapeutic outcome for patients with advanced melanoma. © 2021
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Except where otherwise noted, this item's license is described as Copyright © 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.