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.

P-糖蛋白 (P-gp) 是一种三磷酸腺苷 (ATP) 依赖性药物外排蛋白，通常与癌症化疗中的多药耐药相关。在本报告中，我们使用双荧光共培养模型来研究药物敏感的人卵巢癌细胞系 (OVCAR-8-DsRed2) 及其过度表达 P-gp 的耐药亚系 (NCI/ADR-RES) 的种群动态。 -EGFP) 在光动力疗法 (PDT)-olaparib 联合方案过程中。未经处理，OVCAR-8-DsRed2 细胞比 NCI/ADR-RES-EGFP 细胞生长得更快。奥拉帕尼治疗使癌细胞总数减少了 70±4%，但选择用于抗性 NCI/ADR-RES-EGFP 群体，因为奥拉帕尼是 P-gp 泵的外排底物。本研究使用 FDA 批准的苯并卟啉衍生物 (BPD) 光敏剂或其脂质化制剂（（16：0)LysoPC-BPD) 杀死 OVCAR-8 细胞并降低奥拉帕尼耐药细胞具有选择性优势的可能性。三个循环的 PDT 有效地将总细胞数减少了 66±3%，同时将敏感细胞和抗性细胞的种群比例稳定在大约 1:1。奥拉帕尼治疗和 PDT 的组合增强了 PARP 裂解和脱氧核糖核酸 (DNA) 损伤，进一步将癌细胞总数降低至 10±2%。我们还表明，与使用 olaparib 和 BPD 相比，olaparib 和基于 (16:0) LysoPC-BPD 的 PDT 的组合在减轻抗性 NCI/ADR-RES-EGFP 细胞的选择方面的效率高达 18 倍。基于 PDT。这些研究表明 PDT 可能会提高奥拉帕尼的有效性，