Effects of Doxycycline on Cancer Cells in Vitro and in Vivo

M ortality from cancer is usually due to metastatic disease, which represents the uncontrolled proliferation of cells that no longer respond to the normal regulatory controls of the organism (Silverberg et al, 1990). There are several factors which may accelerate metastasis, including: increased extracellular matrix degradation, due to increased matrix metalloproteinase (MMP) activity, which can facilitate tumor spread (Liotta et al, 1980; DeClerck et al, 1992; Azzam et al, 1993); increased angiogenesis, which is related, at least in part, to elevated MMP activity, permitting the hematogenous spread of tumors (Moscatelli and Rifkin, 1988; Tamargo et al, 1991); and decreased apoptosis, or programmed cell death, in cancer cells, allowing the abnormal cells to escape one of the principal mechanisms for their removal and survive to spread through the body (Armstrong et al, 1992; Furuya et al, 1994). We have been examining the effects of doxycycline, a synthetic tetracycline (TCN), on several human cancer cell lines in vitro, as well as in vivo in the athymic mouse/ xenograft model of metastatic human breast cancer produced by orthotopic implantation of the human breast adenocarcinoma cell line, MDA-MB-435, into the inframammary fat pads of athymic mice. The ability of doxycycline and other TCNs to inhibit MMP activity has been described in the literature. We have shown that doxycycline suppresses MMP activity and cell proliferation in this and other cancer cell lines. We hypothesize that doxycycline inhibits tumor growth in breast and other cancers by a direct effect on the regulation of cell proliferation, which may be distinct from its ability to inhibit MMP activity.