2. Academic Validation
  3. Quassinoid analogs exert potent antitumor activity via reversible protein biosynthesis inhibition in human colorectal cancer

Quassinoid analogs exert potent antitumor activity via reversible protein biosynthesis inhibition in human colorectal cancer

  • Biochem Pharmacol. 2023 Apr 26;115564. doi: 10.1016/j.bcp.2023.115564.
Ning Wei 1,  James Burnett 2,  Desirae L Crocker 2,  Yixian Huang 3,  Song Li 3,  Peter Wipf 4,  Edward Chu 5,  John C Schmitz 6
Affiliations

Affiliations

  • 1 Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, United States; Montefiore Einstein Cancer Center, Cancer Therapeutics Program, Albert Einstein College of Medicine, Bronx, NY, United States. Electronic address: ning.wei@einsteinmed.edu.
  • 2 Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, United States.
  • 3 Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States.
  • 4 Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, United States; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, United States.
  • 5 Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, United States; Montefiore Einstein Cancer Center, Cancer Therapeutics Program, Albert Einstein College of Medicine, Bronx, NY, United States.
  • 6 Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, United States. Electronic address: schmitzjc@upmc.edu.
PMID: 37116665 DOI: 10.1016/j.bcp.2023.115564
Abstract

Cellular protein synthesis is accelerated in human colorectal Cancer (CRC), and high expression of protein synthesis regulators in CRC patients is associated with poor prognosis. Thus, inhibition of protein synthesis may be an effective therapeutic strategy for CRC. We previously demonstrated that the quassinoid bruceantinol (BOL) had antitumor activity against CRC. Herein, potent tumor growth suppression (>80%) and STAT3 inhibition was observed in two different mouse models following BOL administration. Loss of body and spleen weight was observed but was eliminated upon nanoparticle encapsulation while maintaining strong antitumor activity. STAT3 siRNA knockdown exhibited modest suppression of cell proliferation. Surprisingly, STAT3 inhibition using a PROTAC degrader (SD-36) had little effect on Cancer cell proliferation suggesting the possibility of additional mechanism(s) of action for quassinoids. BOL-resistant (BR) cell lines, HCT116BR and HCA7BR, were equally sensitive to standard CRC therapeutic agents and known STAT3 inhibitors but resistant to homoharringtonine (HHT), a known protein synthesis inhibitor. The ability of quassinoids to inhibit protein synthesis was dependent on the structure of the C15 sidechain. Of note, BOL did not inhibit protein synthesis in normal human colon epithelial cells whereas HHT and napabucasin remained effective in these normal cells. Novel quassinoids were designed, synthesized, and evaluated in pre-clinical CRC models. Treatment with the most potent analog, 5c, resulted in significant inhibition of cell proliferation and protein synthesis at nanomolar concentrations. These quassinoid analogs may represent a novel class of protein synthesis inhibitors for the treatment of human CRC.

Keywords

Colorectal cancer; Protein synthesis; Quassinoid analogs.

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