Enhanced phosphatidylserine-selective cancer therapy with irradiation and SapC-DOPS nanovesicles
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Harold W. Davis1, Subrahmanya D. Vallabhapurapu1, Zhengtao Chu1, Swarajya L. Vallabhapurapu1, Robert S. Franco1, Michelle Mierzwa2, William Kassing2, William L. Barrett2 and Xiaoyang Qi1,3
1Division of Hematology/Oncology, Translational Research Laboratory, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
2Department of Radiation Oncology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
3Division of Human Genetics, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
Xiaoyang Qi, email: firstname.lastname@example.org
Keywords: radiotherapy-induced resistance; surface phosphatidylserine-selective; cancer cell death; SapC-DOPS nanovesicles; combined-treatment enhancement
Received: August 15, 2018 Accepted: December 29, 2018 Published: January 25, 2019
Normal living cells exhibit phosphatidylserine (PS) primarily within the intracellular leaflet of the plasma membrane. In contrast, viable cancer cells have high levels of PS on the external surface, and exhibit a broad range of surface PS, even within specific types of cancer. Agents that target surface PS have recently been developed to treat tumors and are expected to be more effective with higher surface PS levels. In this context, we examined whether surface PS is increased with irradiation. In vitro irradiation of cancer cell lines selected surviving cells that had higher surface PS in a dose- and time-dependent manner. This was more pronounced if surface PS was initially in the lower range for cancer cells. Radiation also increased the surface PS of tumor cells in subcutaneous xenografts in nude mice. We found an inverse relationship between steady state surface PS level of cancer cell lines and their sensitivity to radiation-induced cell death. In addition, serial irradiation, which selected surviving cells with higher surface PS, also increased resistance to radiation and to some chemotherapeutic drugs, suggesting a PS-dependent mechanism for development of resistance to therapy. On the other hand, fractionated radiation enhanced the effect of a novel anti-cancer, PS-targeting drug, SapC-DOPS, in some cancer cell lines. Our data suggest that we can group cancer cells into cells with low surface PS, which are sensitive to radiation, and high surface PS, which are sensitive to SapC-DOPS. Combination of these interventions may provide a potential new combination therapy.
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