Novel indoline analogues reverse resistant breast cancer via p-glycoprotein inhibition and apoptotic genes modulation

Abstract

Multidrug resistance (MDR) of breast cancer is an important obstacle nowadays; thus, introducing novel chemotherapies that can overcome this problem is mandatory. Breast cancer resistant cells are characterized by an overexpression of P-glycoprotein (P-gp); thus, providing inhibitors of this protein could be a trendy solution to the MDR obstacle. In the present study, novel indoline analogues 3, 6, (8a-c), (11a-c), (12a-c), 14, (17a-c), (19a,b), 21, and 23 were synthesized and conducted for cytotoxicity against breast cancer sensitive MCF-7 and resistant MCF-7-R cells. We found that benzylidenethiazol derivative 17a had the highest cytotoxic effect and the lowest IC<inf>50</inf> value against cancer cells and was able to reverse the cancer resistance in MCF-7-R cells. Moreover, we investigated the synthesized derivatives against WI38 normal cells to test their targetability against cancerous cells. Intriguingly, all the derivatives recorded slight non-significant decrease in cell viability with undetectable IC<inf>50</inf> values. To track the mechanistic approach of the cancer cell death, we investigated the potentiality of derivative 17a against P-gp, which is overexpressed in resistant MCF-7-R cells mathematically using molecular docking and experimentally using an ELISA assay. All studies showed that the derivative 17a can inhibit P-gp significantly with strong binding affinity, suggesting its potentiality as an effective inhibitor and an apoptotic inducer through upregulation of Bax gene and downregulation of Bcl-2 gene. In conclusion, compound 17a can promote cytotoxicity of resistant MCF-7-R cells through induction of apoptosis and inhibition of P-gp with minimal cytotoxic effect against normal cells.