Glycol porphyrin derivatives and temoporfin elicit resistance to photodynamic therapy by different mechanisms

Abstract

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.

Characterisation of resistance mechanisms developed by basal cell carcinoma cells in response to repeated cycles of Photodynamic Therapy

“…This could point to a larger cancer stem cell component in the resistant populations 47 ; although this should be confirmed. Similar results were obtained with the squamous cell carcinoma SCC-13 17 , 48 and the mammary carcinoma 4T1 49 . Regarding to the type of tumours developed, no relevant histological differences were observed, except for the presence of osteoid tissue in the tumours generated from BSZ P, CSZ P and CSZ 10 th G. These histological features presented similarities to one uncommon human BCC subtype, the basal cell carcinosarcoma, very rare in patients and with an equivalent metastasis capacity to conventional BCCs.…”

Integration Analysis of Differential Expressed Genes Regulated by Differential Methylated Regions for Predicting Prognosis in Human Colon Cancer

“…Some reports found that retinoid acid binding receptor inhibited cancer cell apoptosis by regulating miR-22/NUR77 axis (21,22). Interestingly, from the results of KEGG pathway enrichment analysis, we found that the genes mainly enriched in molecular metabolism, being consistent with BP of GO enrichment, and the drug, retinoid and porphyrin metabolism are proved involving in irregulated tumor cell metabolism, and resulted in chemotherapy resistant (23).…”

Epigallocatechin Gallate Enhances MAL-PDT Cytotoxic Effect on PDT-Resistant Skin Cancer Squamous Cells

“…This recurrence could be associated with cell resistance to PDT, however there are no reports on resistance to this therapy as there is in radiation therapy or chemotherapy in the treatment of other cancers [21]. Despite this lack of information, several studies have tried to clarify the mechanisms involved in PDT resistance, mainly using cancer cell lines [22][23][24][25].…”