The HIV protease inhibitor nelfinavir is currently under investigation as a new anti-cancer drug. Several studies have shown that nelfinavir induces cell cycle arrest, endoplasmic reticulum stress, autophagy, and apoptosis in cancer cells. Here, the effect of nelfinavir on human breast cancer cells was examined, and potential combination treatment options investigated.

The effects of nelfinavir and tamoxifen on the human breast cancer cell lines MCF7, T47D, MDA-MB-453, and MDA-MB-435 were tested by analyzing their effects on cell viability (via 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay), apoptosis (annexin binding, poly [ADP-ribose] polymerase (PARP) cleavage), autophagy (autophagy marker light chain 3B (LC3B) expression), endoplasmic reticulum stress (binding protein (BiP) and activating transcription factor 3 (ATF3) expression), and the occurrence of oxidative stress (intracellular glutathione level).

Nelfinavir induced apoptosis in all of the four breast cancer cell lines tested, although the extent of autophagy and endoplasmic reticulum stress varied among the cell lines. The concentration of nelfinavir needed for an efficient induction of apoptosis in breast cancer cells could be reduced from 15 ug/ml to 6 ug/ml when combined with tamoxifen. At a concentration of 6 ug/ml, tamoxifen substantially enhanced the endoplasmic reticulum stress reaction in those cell lines that responded to nelfinavir with BiP upregulation (MCF7, T47D), and enhanced autophagy in cell lines that responded to nelfinavir treatment with LC3B upregulation (MDA-MB-453). Although tamoxifen has been described to be able to induce oxidative stress at concentrations similar to those applied in this study (6 ug/ml), we observed that nelfinavir but not tamoxifen reduced the intracellular glutathione levels of breast cancer cells within hours of application by up to 32 %, suggesting the induction of oxidative stress was an early event and an additional cause of the apoptosis induced by nelfinavir.

The results demonstrate that nelfinavir may be an effective drug against breast cancer and could be combined with tamoxifen to enhance its efficacy against breast cancer cells. Moreover, the cytotoxic effect of a tamoxifen and nelfinavir combination was independent of the oestrogen receptor status of the analysed breast cancer cells, suggesting a potential benefit of a combination of these two drugs even in patients with no hormone-responsive tumours. We therefore recommend that clinical studies on nelfinavir with breast cancer patients should include this drug combination to analyse the therapeutic efficacy as well as the safety and tolerability of this potential treatment option.

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