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

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

  • Mol Cancer Ther. 2018 Oct;17(10):2123-2135. doi: 10.1158/1535-7163.MCT-17-1195.
Alexandria N Young 1,  Denisse Herrera 1,  Andrew C Huntsman 2,  Melissa A Korkmaz 3,  Daniel D Lantvit 1,  Sarmistha Mazumder 4,  Shamalatha Kolli 4,  Christopher C Coss 4,  Salane King 4,  Hongyan Wang 4,  Steven M Swanson 5,  A Douglas Kinghorn 2,  Xiaoli Zhang 6,  Mitch A Phelps 4,  Leslie N Aldrich 3,  James R Fuchs 2,  Joanna E Burdette 7
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.
  • 2 Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio.
  • 3 Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois.
  • 4 Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio.
  • 5 Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, Madison, Wisconsin.
  • 6 Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, Ohio.
  • 7 Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois. joannab@uic.edu.
PMID: 30018048 DOI: 10.1158/1535-7163.MCT-17-1195
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 holds promise as a potential, novel chemotherapeutic and demonstrates the effectiveness of targeting the autophagic pathway as a viable strategy for combating ovarian Cancer. Mol Cancer Ther; 17(10); 2123-35. ©2018 AACR.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-122650
    98.43%, Autophagy抑制剂
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