2. Academic Validation
  3. Physachenolide C induces complete regression of established murine melanoma tumors via apoptosis and cell cycle arrest

Physachenolide C induces complete regression of established murine melanoma tumors via apoptosis and cell cycle arrest

  • Transl Oncol. 2022 Jan;15(1):101259. doi: 10.1016/j.tranon.2021.101259.
Anngela C Adams 1,  Anne M Macy 2,  Paul Kang 3,  Karla F Castro-Ochoa 4,  E M Kithsiri Wijeratne 5,  Ya-Ming Xu 6,  Manping X Liu 7,  Alexandra Charos 8,  Marcus W Bosenberg 9,  A A Leslie Gunatilaka 10,  Aparna R Sertil 11,  K Taraszka Hastings 12
Affiliations

Affiliations

  • 1 University of Arizona College of Medicine Phoenix, 425 N. 5th St., Phoenix, AZ 85004, United States. Electronic address: [email protected].
  • 2 University of Arizona College of Medicine Phoenix, 425 N. 5th St., Phoenix, AZ 85004, United States. Electronic address: [email protected].
  • 3 Mel and Enid Zuckerman College of Public Health, 714 E. Van Buren St., Phoenix, AZ 85006, United States. Electronic address: [email protected].
  • 4 University of Arizona College of Medicine Phoenix, 425 N. 5th St., Phoenix, AZ 85004, United States. Electronic address: [email protected].
  • 5 Southwest Center for Natural Products Research, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, 250 E. Valencia Rd., Tucson, AZ 85706, United States. Electronic address: [email protected].
  • 6 Southwest Center for Natural Products Research, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, 250 E. Valencia Rd., Tucson, AZ 85706, United States. Electronic address: [email protected].
  • 7 Southwest Center for Natural Products Research, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, 250 E. Valencia Rd., Tucson, AZ 85706, United States. Electronic address: [email protected].
  • 8 Department of Dermatology, Yale University, 333 Cedar St., New Haven, CT 06520, United States. Electronic address: [email protected].
  • 9 Department of Dermatology, Yale University, 333 Cedar St., New Haven, CT 06520, United States. Electronic address: [email protected].
  • 10 Southwest Center for Natural Products Research, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, 250 E. Valencia Rd., Tucson, AZ 85706, United States; University of Arizona Cancer Center, University of Arizona, 1515 N. Campbell Ave., Tucson, AZ 85724, United States. Electronic address: [email protected].
  • 11 University of Arizona College of Medicine Phoenix, 425 N. 5th St., Phoenix, AZ 85004, United States. Electronic address: [email protected].
  • 12 University of Arizona College of Medicine Phoenix, 425 N. 5th St., Phoenix, AZ 85004, United States; University of Arizona Cancer Center, University of Arizona, 1515 N. Campbell Ave., Tucson, AZ 85724, United States. Electronic address: [email protected].
PMID: 34735896 DOI: 10.1016/j.tranon.2021.101259
Abstract

Melanoma 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.

Keywords

Melanoma; Mouse model; Natural products.

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