Metastatic
cancers account for more than 90% of
cancer mortality. The
metastasis of all
cancers is critically mediated by
enzymes that degrade extracellular matrix. Aggressive
tumors are characterized by an imbalance between
enzymes that degrade ECM and endogenous inhibitors of the
enzymes.
Matrix metalloproteinases (
MMPs) make up the majority of ECM degrading
enzymes implicated in
cancer metastasis. The potent
MMP inhibitory activities of
tetracyclines, especially their chemically modified analogs, combined with their relatively well tolerated pharmacological profile, led several researchers to investigate their anticancer potential in a variety of
cancers, including
melanoma, lung, breast and
prostate cancers. Chemically modified non-
antibiotic tetracyclines (CMTs or COL) were tested using
tumors of prostate, breast and
melanomas. Some of these CMTs, notably,
CMT-3 and
CMT-308 significantly inhibited not only invasive potential and
MMP activity, but also inhibited cell proliferation by inducing cell cycle arrest and apoptosis.
CMT-3 and
CMT-308 were significantly more potent than
doxycycline or
minocycline in inhibiting
tumor cell-derived
MMPs and inducing apoptosis in vitro and in vivo.
CMT-3 (COL-3) showed potent inhibition of
tumor growth in xenografts and in bone metastatic models of
prostate cancer. Similar results were also reported in
melanoma and
breast cancer models. The mechanism by which CMTs kill
tumor cells is via generation of
hydroxyl free radicals ([
OH](-)) which permeate and depolarize mitochondria, which in turn activates
caspase mediated apoptosis. Analysis of
tumor tissues from
CMT-3 treated rats demonstrated reduction in angiogenesis and increase in apoptosis; both emerged as mechanisms of CMT action. These observations led to testing the efficacy of
CMT-3 in human clinical trials against several types of
cancer with significant outcomes, which are described in the next chapter of this issue.