Ester derivatives of salinomycin efficiently eliminate breast cancer cells via ER-stress-induced apoptosis

Area of Science:

• Biochemistry
• Oncology
• Medicinal Chemistry

Background:

• Salinomycin (SAL), a polyether ionophore, targets breast cancer cells, including stem-like cells.
• Semi-synthetic SAL amides and esters demonstrate anticancer properties with potentially reduced toxicity compared to standard chemotherapy.
• Limited research exists on the activity and mechanisms of SAL derivatives against breast cancer.

Purpose of the Study:

• To confirm the anti-breast cancer activity of SAL.
• To investigate the potential of SAL C1 amide and ester analogs against breast cancer cells, including MDA-MB-231.
• To elucidate the mechanisms of action for potent SAL derivatives.

Main Methods:

• Synthesis and derivatization of salinomycin at the C1 carboxyl group.
• In vitro evaluation of anticancer activity against MCF-7 and MDA-MB-231 breast cancer cell lines.
• Analysis of protein expression (p-eIF2α, IRE1α, γH2AX) and DNA damage markers (8-oxoG).

Main Results:

• SAL esters were more potent than native SAL and its amide analogs.
• Compounds 5 and 7 (trifluoroethyl and benzotriazole SAL esters) significantly increased p-eIF2α and IRE1α protein levels.
• Elevated levels of DNA damage indicators (γH2AX, 8-oxoG) were observed in treated cells.

Conclusions:

• SAL ester derivatives exhibit significant potential for destroying breast cancer cells, particularly aggressive types.
• The mechanism involves the interplay between endoplasmic reticulum stress and DNA damage response pathways.
• SAL esters represent promising candidates for novel breast cancer therapeutics.