Chemoresistance is one of the leading causes of the failure of
chemotherapy. Overexpression of
P-glycoprotein (P-gp) in
cancer cells is one of the most important contributing factors toward the development of chemoresistance. This study was designed to synthesize the derivatives of dihydronaphthyl and to evaluate the P-gp inhibition activity of these compounds. Among all the compounds, PGP-41 showed the most potent P-gp inhibition activity in colorectal
adenocarcinoma LS-180 cells. This compound showed potent P-gp inhibition activity in chemoresistant ovarian cell line NCI/ADR-RES.
Paclitaxel is one of the first lines of drugs for treating
ovarian cancer and is a substrate of P-gp; therefore, NCI/ADR-RES cells are highly resistant to treatment with
paclitaxel. Based on this information, we evaluated PGP-41 to overcome the
paclitaxel resistance of NCI/ADR-RES cells. PGP-41 was able to sensitize the NCI/ADR-RES cells to the treatment of
paclitaxel, which was evident by the reduced IC50 value of
paclitaxel from 6.64 μM to 0.12 μM. The sensitization of NCI/ADR-RES cells by PGP-41 was comparable to that of
elacridar and Zosuquidar. Further studies revealed that the PGP-41 exerts its effect by downregulating the expression of P-gp. Reduction of P-gp activity leads to the accumulation of higher intracellular concentration of
paclitaxel, and thus allowing it to interact with its targets, which further helps in its increased efficacy.
Paclitaxel was able to arrest the sensitized NCI/ADR-RES cells into G2M phase, which ultimately led to the induction of apoptotic
proteins and the death of
cancer cells. Being a different scaffold from zosuquidar and
elacridar, further studies are required to develop PGP-41 into a potential
drug to overcome chemoresistance in
cancer cells.