Cytotoxic effects of alkyl-phospholipids (Erufosine and Perifosine) in combination with cell cycle check point inhibitor (ATM) in breast cancer cells

Abstract

Background: Breast cancer is the most common cancer in females with continuously growing incidence over the last two decades. In advanced stages, the disease is difficult to manage and imposes a major morbidity and mortality burden. Available treatment options are limited with a moderate capacity to cure. Situation demands to look for alternative therapeutic compounds. Alkyl-phospholipids (ALPs) are attractive options, and the two latest generations of this class (erufosine and perifosine) have shown substantial anticancer potential against cancer. In addition, ATM, an important factor during DNA damage/response, has come up for its corresponding therapeutic relevancy. Combining the two above-mentioned classes can lead to effective therapeutic options against breast cancer.

Methods: Toxic effects of the selected compounds on breast cancer cell lines were determined by MTT dye reduction assay. The selected cell lines (MDA-MB-231 and MCF-7) were cultured in 96-well plates and exposed to various concentrations of the compounds for three different time intervals (24, 48 and 72 hours). Following the exposure of cells with the agents, expression modulations in CDKN family of genes were monitored at transcriptome level via real-time PCR methodology.

Results: Exposure with the ALPs and ATM inhibited cell proliferation of the two breast cancer cell lines. Overall, ALPs were more capable of inhibiting cell proliferation. Combination of ALPs and ATM worked synergistically and reduced the cellular proliferation more effectively especially in MCF-7 cells. ALPs and the selected ATM inhibitor induced the expression of CDKN family members. Overall, the induction was maximally seen in CDKN1A gene with a maximum induction level of 40fold in MCF-7 cells. 

Conclusion: ALPs and ATM have the potential to inhibit proliferation of breast cancer cells and can support each other synergistically. Important cell cycle inhibitor genes like CDKN family can be induced by using above mentioned compounds.