Inhibition of cell proliferation, invasion, tumor growth and metastasis by an oral non‐antimicrobial tetracycline analog (COL‐3) in a metastatic prostate cancer model

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Abstract
Antibiotic forms of tetracycline exhibit antitumor activity in some tumor models. However, their low in vivo efficacy and associated morbidity limit their long‐term application in cancer therapy. This report appraises the efficacy of doxycycline (DC) and non‐antimicrobial, chemically modified tetracyclines (CMTs) against prostate cancer. Both DC and several CMTs inhibited prostate tumor cell proliferation in vitro. Some of the CMTs were significantly more potent than DC. One of the CMTs, 6‐deoxy, 6‐demethyl, 4‐de‐dimethylamino tetracycline (CMT‐3, COL‐3), was the most potent inhibitor (50% inhibition dose [GI50] ≤ 5.0 μg/ml). Exposure of tumor cells to CMT‐3 induced both apoptosis and necrosis. Mitochondrial depolarization and increased levels of reactive hydroxyl radicals were also observed in cells treated with CMT‐3. Cell cycle arrest at the G0/G1 compartment was observed in CMT‐3‐ and DC‐treated cells. DC and CMTs also inhibited the invasive potential of the tumor cells in vitro, from 10% (CMT‐6) to >90% (CMT‐3). CMT‐3 and DC decreased matrix metalloproteinase (MMP)‐2, tissue inhibitor of MMP (TIMP)‐1 and TIMP‐2 secretion in treated cultures and inhibited activity of secreted MMPs, CMT‐3 was a stronger inhibitor. Daily oral gavage of DC and CMT‐3 inhibited tumor growth and metastasis in the Dunning MAT LyLu rat prostate tumor. Decreases in tumor growth (27–35%) and lung metastases were observed (28.9 ± 15.4 sites/animal [CMT‐3‐treated] versus 43.6 ± 18.8 sites/animal [DC‐treated] versus 59.5 ± 13.9 [control]; p < 0.01]. A delay in tumor growth (27 ± 9.3%, p < 0.05), reduction in metastases (58 ± 8%) and decrease in tumor incidences (55 ± 9%, CMT‐3‐treated) were also observed, when rats were predosed for 7 days. No significant drug‐induced morbidity was observed in any of the animals. These results, along with a recently concluded clinical trial, suggest a potential use of CMT‐3 as an oral, nontoxic drug to treat metastatic prostate and other cancers.