Phyllanthusmin Derivatives Induce Apoptosis and Reduce Tumor Burden in High-Grade Serous Ovarian Cancer by Late-Stage Autophagy Inhibition

Molecular Cancer Therapeutics
Alexandria N YoungJoanna E Burdette

Abstract

High-grade serous ovarian cancer (HGSOC) is a lethal gynecological malignancy with a need for new therapeutics. Many of the most widely used chemotherapeutic drugs are derived from natural products or their semi-synthetic derivatives. We have developed potent synthetic analogues of a class of compounds known as phyllanthusmins, inspired by natural products isolated from Phyllanthus poilanei Beille. The most potent analogue, PHY34, had the highest potency in HGSOC cell lines in vitro and displayed cytotoxic activity through activation of apoptosis. PHY34 exerts its cytotoxic effects by inhibiting autophagy at a late stage in the pathway, involving the disruption of lysosomal function. The autophagy activator, rapamycin, combined with PHY34 eliminated apoptosis, suggesting that autophagy inhibition may be required for apoptosis. PHY34 was readily bioavailable through intraperitoneal administration in vivo where it significantly inhibited the growth of cancer cell lines in hollow fibers, as well as reduced tumor burden in a xenograft model. We demonstrate that PHY34 acts as a late-stage autophagy inhibitor with nanomolar potency and significant antitumor efficacy as a single agent against HGSOC in vivo This class of compounds hold...Continue Reading

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Nov 6, 2018·International Journal of Molecular Sciences·Xing-Xian GuoJing Li
Mar 25, 2020·Journal of Natural Medicines·Shinya OkuboTakuhiro Uto
Apr 24, 2020·Cancer Cell International·Xiao-Yu YanJing Su
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Feb 16, 2021·Fitoterapia·Isoo YounChun-Tao Che
Mar 5, 2019·Journal of Natural Products·Yulin RenA Douglas Kinghorn

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