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Small-Molecule Natural Product Physachenolide C Potentiates Immunotherapy Efficacy by Targeting BET Proteins

  1. Author:
    Tewary,Poonam
    Brooks, Alan D.
    Xu, Ya-Ming
    Wijeratne, E. M. Kithsiri
    Babyak, Ashley L.
    Back, Timothy C.
    Chari,Raj
    Evans,Christine
    Henrich,Curtis
    Meyer,Thomas
    Edmondson,Elijah
    de Aquino, Maria T. Prudente
    Kanagasabai, Thanigaivelan
    Shanker, Anil
    Gunatilaka, A. A. Leslie
    Sayers, Thomas J.

  2. Author Address

    Frederick Natl Lab Canc Res, Basic Sci Program, Frederick, MD USA.Univ Arizona, Southwest Ctr Nat Prod Res, Sch Nat Resources & Environm, Coll Agr & Life Sci, Tucson, AZ 85706 USA.NCI, Canc & Inflammat Program, Frederick, MD 21701 USA.Frederick Natl Lab Canc Res, Genome Modificat Core Lab, Frederick, MD USA.NCI, CCR Collaborat Bioinformat Resource, NIH, Bethesda, MD 20892 USA.Frederick Natl Lab Canc Res, Adv Biomed Computat Sci, Frederick, MD USA.Frederick Natl Lab Canc Res, Mol Histopathol Lab, Frederick, MD USA.Meharry Med Coll, Sch Med, Dept Biochem Canc Biol Neurosci & Pharmacol, Nashville, TN 37208 USA.Vanderbilt Ingram Canc Ctr, Host Tumor Interact Res Program, Nashville, TN USA.Vanderbilt Univ, Sch Med, Vanderbilt Inst Infect Immunol & Inflammat, Nashville, TN USA.
    1. Year: 2021
    2. Date: Jun 15
    3. Epub Date: 2021 04 09
  2. Journal: Cancer Research
  3. AMER ASSOC CANCER RESEARCH,
    1. 81
    2. 12
    3. Pages: 3374-3386
  5. Type of Article: Article
  6. ISSN: 0008-5472
  1. Abstract:

    Screening for sensitizers of cancer cells to TRAIL-mediated apoptosis identified a natural product of the 17 beta-hydroxywithanolide (17-BHW) class, physachenolide C (PCC), as a promising hit. In this study, we show that Pa: was also able to sensitize melanoma and renal carcinoma cells to apoptosis in response not only to TRAIL, but also to the synthetic polynucleotide poly I:C, a viral mimetic and immune activator, by reducing levels of antiapoptotic proteins cFLIP and Livin. Both death receptor and TLR3 signaling elicited subsequent increased assembly of a proapoptotic ripoptosome signaling complex. Administration of a combination of PCC and poly I:C in human M14 melanoma xenograft and a syngeneic B16 melanoma model provided significant therapeutic benefit as compared with individual agents. In addition, PCC enhanced melanoma cell death in response to activated human T cells in vitro and in vivo in a death ligand-dependent manner. Biochemical mechanism-ofaction studies established bromo and extraterminal domain (BET) proteins as major cellular targets of PCC. Thus, by targeting of BET proteins to reduce antiapoptotic proteins and enhance caspase-8-dependent apoptosis of cancer cells, PCC represents a unique agent that can potentially be used in combination with various immunotherapeutic approaches to promote tumor regression and improve outcome.

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External Sources

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  2. DOI: 10.1158/0008-5472.CAN-20-2634
  3. PMID: 33837043
  4. View record in Web of Science®
  5. WOS: 000662284300021

Library Notes

  1. Fiscal Year: FY2020-2021
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