Selective modulation of collagenase 1 gene expression by the chemotherapeutic agent doxorubicin

Matrix metalloproteinases (MMPs) play a crucial role in tumor cell invasion and metastasis due to their ability to digest basement membrane and extrac ellular matrix components, thereby facilitating cell movement through conne ctive tissues. At noncytotoxic concentrations, i.e., concentrations lower t han those normally used in cancer chemotherapy, the anthracycline doxorubic in specifically inhibited collagenase 1 (MMP-1) gene expression in the high ly invasive and metastatic human melanoma cell line A2058. This inhibition was specific for collagenase 1 because it did not affect the expression of two other MMPs, gelatinase A (MMP-2) and gelatinase B (MMP-9). The reductio n in collagenase 1 expression correlated with a decrease in the invasive ab ility of tumor cells through a collagen type I matrix and was independent o f the cytotoxic and antiproliferative effects usually associated with this anticancer drug. The selective modulation of collagenase 1 expression by no ntoxic doses of doxorubicin suggests a novel application for this chemother apeutic agent, perhaps in combination therapy, because it decreases the inv asive/metastatic potential of melanoma cells that are otherwise unaffected by this drug.