| Cancer remains a deadly disease and there is a great medical need for improved therapies. Therefore, in the present study we set out to investigate the anti-cancer potential of novel drug combinations in human glioblastoma and breast cancer cell lines in vitro. We combined two types of compounds. One type was represented by agents that were already approved by the FDA for indications outside of cancer therapy; these included the human immunodeficiency virus (HIV) protease inhibitor nelfinavir (Viracept) and the cyclooxygenase-2 (COX-2) inhibitor celecoxib (Celebrex). The other type included novel compounds that are not yet FDA-approved, such as 2,5-dimethyl-celecoxib (DMC) and similar analogs that are unable to inhibit COX-2. We found that several of these novel combinations caused aggravated endoplasmic reticulum (ER) stress and resulted in pronounced cytotoxicity via the induction of apoptosis (programmed cell death). Interestingly, in some instances the cytotoxic effects could be reduced by the inclusion of rebamipide, an anti-ulcer drug, and our results indicate that this effect was due to rebamipide's ability to prevent major perturbations in intracellular calcium levels. Taken together, our study shows that the anticancer effects of nelfinavir, celecoxib, and DMC can be enhanced when carefully chosen combinations of these and similar drugs are applied. As well, changes in intracellular calcium homeostasis appear to play an important part in triggering tumor cell death by these compounds. Thus, our findings support the notion that combinations of these small-molecule compounds should be considered as a potential new therapeutic strategy in cancer therapy. |
