Evolutionary dynamics of cancer multidrug resistance in response to olaparib and photodynamic therapy

Translational Oncology

Dana M. Roque¹  Jocelyn Reader²  Huang-Chiao Huang²  Yan Baglo³  Aaron J. Sorrin³  Cindy Liu³  Xiaocong Pu³ 

[1] Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore 21201 MD, USA;Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore 21201 MD, USA;Fischell Department of Bioengineering, University of Maryland, College Park 20742 MD, USA;

关键词: Multidrug resistance;    ATP-binding cassette transporters;    Photodynamic therapy;    Poly (ADP-ribose) polymerase inhibitors;    Cancer evolution;   

DOI  :  

来源: DOAJ

【 摘 要 】

P-glycoprotein (P-gp) is an adenosine triphosphate (ATP)-dependent drug efflux protein commonly associated with multidrug resistance in cancer chemotherapy. In this report, we used a dual-fluorescent co-culture model to study the population dynamics of the drug sensitive human ovarian cancer cell line (OVCAR-8-DsRed2) and its resistant subline that overexpresses P-gp (NCI/ADR-RES-EGFP) during the course of a photodynamic therapy (PDT)-olaparib combination regimen. Without treatment, OVCAR-8-DsRed2 cells grew more rapidly than the NCI/ADR-RES-EGFP cells. Olaparib treatment reduced the total number of cancer cells by 70±4% but selected for the resistant NCI/ADR-RES-EGFP population since olaparib is an efflux substrate for the P-gp pump. This study used the FDA-approved benzoporphyrin derivative (BPD) photosensitizer or its lipidated formulation ((16:0)LysoPC-BPD) to kill OVCAR-8 cells and reduce the likelihood that olaparib-resistant cells would have selective advantage. Three cycles of PDT effectively reduced the total cell number by 66±3%, while stabilizing the population ratio of sensitive and resistant cells at approximately 1:1. The combination of olaparib treatment and PDT enhanced PARP cleavage and deoxyribonucleic acid (DNA) damage, further decreasing the total cancer cell number down to 10±2%. We also showed that the combination of olaparib and (16:0)LysoPC-BPD-based PDT is up to 18-fold more effective in mitigating the selection of resistant NCI/ADR-RES-EGFP cells, compared to using olaparib and BPD-based PDT. These studies suggest that PDT may improve the effectiveness of olaparib, and the use of a lipidated photosensitizer formulation holds promise in overcoming cancer drug resistance.

【 授权许可】

Unknown