CZ-OPENSCREEN: National Infrastructure for Chemical Biology, Institute of Molecular Genetics of the ASCR, v. v. i., Prague, Czech Republic.
Laboratory of Genomics and Bioinformatics, Institute of Molecular Genetics of the ASCR, v. v. i., Prague, Czech Republic.
Sci Rep. 2017 Mar 15;7:44497. doi: 10.1038/srep44497.
The development of drug resistance is a major problem which often occurs during anticancer chemotherapies. Photodynamic therapy (PDT) has been studied as an alternative treatment modality for drug-resistant tumors, however the question of resistance to PDT and potential cross-resistance with chemotherapy has yet to be fully answered. To investigate the mechanism of resistance to PDT, we developed an in vitro experimental model system in a mouse mammary carcinoma cell line 4T1. We used two ethylene glycol derivatives of tetraphenylporphyrin, and tetraphenylchlorin derivative, temoporfin, as photosensitizers (PS). PDT-resistant clones were obtained by exposure to a set concentration of PS followed by irradiation with increasing light doses. PDT resistance to soluble glycol porphyrins was mediated mainly by increased drug efflux through ABCB1 (P-glycoprotein) as we demonstrated by specific ABCB1 knockdown experiments, which in turn rescued the sensitivity of resistant cells to PDT. In contrast, resistance raised to temoporfin, which is generally more lipophilic than glycol porphyrins, elicited mechanism based on sequestration of the drug to lysosomes. The resistance that is acquired from a particular PS could be overcome by using a different PS, which is not susceptible to the same mechanism(s) of resistance. Elucidation of the underlying mechanisms in various types of resistance might facilitate improvements in PDT treatment design.
耐药性的发展是癌症化疗中经常出现的主要问题。光动力疗法（PDT）已被研究作为耐药肿瘤的替代治疗方法，然而，PDT 耐药性以及与化疗的潜在交叉耐药性问题尚未得到充分解答。为了研究对 PDT 的耐药机制，我们在小鼠乳腺肿瘤细胞系 4T1 中建立了体外实验模型系统。我们使用两种乙二醇衍生的四苯基卟啉和四苯基氯代卟啉衍生物替莫泊芬作为光敏剂（PS）。通过暴露于设定浓度的 PS 并随后用递增的光剂量照射来获得 PDT 耐药克隆。我们通过特异性 ABCB1 敲低实验证明，对可溶性乙二醇卟啉的 PDT 耐药性主要是通过 ABCB1（P-糖蛋白）增加药物外排来介导的，这反过来又使耐药细胞对 PDT 的敏感性得以恢复。相比之下，对脂溶性通常高于乙二醇卟啉的替莫泊芬产生的耐药性则是基于将药物隔离到溶酶体中。从特定 PS 获得的耐药性可以通过使用不易受到相同耐药机制影响的不同 PS 来克服。阐明各种类型耐药性的潜在机制可能有助于改进 PDT 治疗设计。
