Combining DNA Damage Induction with BCL-2 Inhibition to Enhance Merkel Cell Carcinoma Cytotoxicity
Year: 2020
Type: article
Abstract: Merkel cell carcinoma (MCC) is a highly lethal skin cancer. MCC tumors rapidly develop resistance to the chemotherapies tested to date. While PD-1/PD-L1 immune checkpoint blockade has demonstrated success in MCC treatment, a significant portion of MCC patients are nonresponsive. Therefore, the pressing need for effective MCC chemotherapies remains. We screened a library of natural products and discovered that one compound, glaucarubin, potently reduced the viability of Merkel cell polyomavirus (MCPyV)-positive MCCs, while remaining nontoxic to primary human fibroblasts and MCPyV-negative MCC cell lines tested. Protein array and Western blot analyses revealed that glaucarubin induces DNA damage and PARP-1 cleavage that correlates with the loss of viability in MCC cells. However, high basal expression of the antiapoptotic factor BCL-2 allowed a subpopulation of cells to survive glaucarubin treatment. Previous studies have shown that, while targeting BCL-2 family proteins significantly decreases MCC cell viability, BCL-2 antisense therapy alone was insufficient to inhibit tumor growth in patients with advanced MCC. We discovered that treatment with an FDA-approved BCL-2 inhibitor in the context of glaucarubin-induced DNA damage led to near complete killing in multiple MCPyV-positive MCC cell lines that express high levels of BCL-2. The combination of DNA damage-induced apoptosis and BCL-2 inhibition thus represents a novel therapeutic strategy for MCPyV-positive MCCs.
Source: Biology
Institutions: University of Pennsylvania, The Wistar Institute
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $1,584
Funders: Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Oregon Health and Science University, University of Pennsylvania, Dana-Farber/Harvard Cancer Center, National Cancer Center, National Institutes of Health, University of Texas MD Anderson Cancer Center, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: G1403651065, G1747053960, G1852790566, G202896860, G2152591659, Mechanism of Brd4-mediated papillomavirus host interactions, G3428346584, G432566759, Chromatin structure maintenance and cancer, G4739483508, G6160060787, G9000000688, G9000127251, G9000138654, Consolidated Basic Cancer Research Program, Penn Skin Biology and Diseases Resource-based Center, Merkel cell polyomavirus infection, host response, and viral oncogenic mechanism
OpenAlex ID: W3007312912