Overexpression of caspase-3 restores sensitivity for drug-induced apoptosis in breast cancer cell lines with acquired drug resistance

In this study, we asked whether overexpression of caspase-3, a central down stream executioner of apoptotic pathways, might sensitize breast cancer cel ls with acquired drug resistance (MT1/ADR) to drug-induced apoptosis, As co ntrol, we employed caspase-3 negative and caspase-3-transfected MCF-7 cells , Whereas mock-transfected MCF-7 cells were resistent to epirubicin, etopos ide and paclitaxel (taxol), the same drugs led to breakdown of nuclear DNA in caspase-3-transfected MCF-7 cells, MT1/ADR cells express low levels of w ild type caspase-3 but show defective caspase activation and apoptosis upon drug exposure. These cells also display a Less efficient activation of the mitochondrial permeability transition. Caspase-3-transfected MT1/ADR clone s showed a 2.8-fold increase in the protein level and a 3.7-fold higher spe cific enzyme activity. Procaspase-3 overexpression was not toxic and did no t affect background apoptosis, Interestingly, procaspase-3-transfected MT1/ ADR cells were more sensitive to cytotoxic drags as compared with vector-tr ansfected controls and DNA fragmentation nearly reached the levels of the o riginal drug sensitive MT1 cells. Thus, overexpression of caspase-3 enhance s chemosensitivity especially in situations where activation of the mitocho ndrial apoptosome is disturbed.