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Combining DNA Damage Induction with BCL-2 Inhibition to Enhance Merkel Cell Carcinoma Cytotoxicity.

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.

SUBMITTER: Liu W

PROVIDER: S-EPMC7168258 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Combining DNA Damage Induction with BCL-2 Inhibition to Enhance Merkel Cell Carcinoma Cytotoxicity.

Liu Wei W Krump Nathan A NA Herlyn Meenhard M You Jianxin J

Biology 20200219 2

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 ( ...[more]

PMID: 32093022

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Project description:Background: Oncogenic transformation is associated with elevated oxidative stress that promotes tumor progression but also renders cancer cells vulnerable to further oxidative insult. Agents that stimulate ROS generation or suppress antioxidant systems can drive oxidative pressure to toxic levels selectively in tumor cells, resulting in oxidative DNA damage to endanger cancer cell survival. However, DNA damage response signaling protects cancer cells by activating DNA repair and genome maintenance mechanisms. In this study, we investigated the synergistic effects of combining the pro-oxidative natural naphthoquinone alkannin with inhibition of DNA repair by PARP inhibitors. Methods and Results: The results showed that sublethal doses of alkannin induced ROS elevation and oxidative DNA damage in colorectal cancer but not normal colon epithelial cells. Blocking DNA repair with the PARP inhibitor olaparib markedly synergized with alkannin to yield synergistic cytotoxicity in colorectal cancer cells at nontoxic doses of both drugs. Synergy between alkannin and olaparib resulted from interrupted repair of alkannin-induced oxidative DNA damage and PARP-trapping, as it was significantly attenuated by NAC or by OGG1 inhibition and the non-trapping PARP inhibitor veliparib did not yield synergism. Mechanistically, the combination of alkannin and olaparib caused intense replication stress and DNA strand breaks in colorectal cancer cells, leading to apoptotic cancer cell death after G2 arrest. Consequently, coadministration of alkannin and olaparib induced significant regression of tumor xenografts in vivo, while each agent alone had no effect. Conclusion: These studies clearly show that combining alkannin and olaparib can result in synergistic cancer cell lethality at nontoxic doses of the drugs. The combination exploits a cancer vulnerability driven by the intrinsic oxidative pressure in most cancer cells and hence provides a promising strategy to develop broad-spectrum anticancer therapeutics.

Dataset Information

Combining DNA Damage Induction with BCL-2 Inhibition to Enhance Merkel Cell Carcinoma Cytotoxicity.

Publications

Combining DNA Damage Induction with BCL-2 Inhibition to Enhance Merkel Cell Carcinoma Cytotoxicity.

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