期刊
BIOLOGY-BASEL
卷 9, 期 2, 页码 -出版社
MDPI
DOI: 10.3390/biology9020035
关键词
Merkel cell carcinoma; DNA damage induction; BCL2 inhibitor ABT-199
类别
资金
- NIH [R01CA187718]
- NCI Cancer Center Support Grant [NCI P30 CA016520]
- Penn CFAR award [P30 AI 045008]
- Miriam and Sheldon G. Adelson Medical Research Foundation
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.
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