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Cytotoxic Activity and Inhibition of Tumor Cell Invasion by Derivatives of a Chemically Modified Tetracycline CMT-3 (COL-3)

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Tetracyclines such as chlortetracycline and doxycycline with antimicrobial activity were reported to possess cytostatic and cytotoxic activity against mammalian tumor cells, often at high doses. Non-antimicrobial chemically modified tetracyclines (CMTs), with limited systemic toxicity but with significant tumor cell toxicity and anti-metastatic activity, are attractive for long term treatment for cancer. We recently reported one such CMT, 6-deoxy, 6-demethyl 4-dedimethylamino tetracycline (CMT-3) is a potent anti-tumor and anti-metastatic drug. Here we report on the anti-cell proliferation and anti-invasive activity of five nitro derivatives of CMT-3 (CMT-3N). All the five CMT-3Ns (CMT-302, CMT-303, CMT-306, CMT-308 and CMT-316) inhibited in vitro cell proliferation of prostate cancer cells. The 50 percent growth inhibition concentration (IC 50 ) of CMT-3Ns was similar to that of CMT-3. Although CMT-3 was by far the most potent anti-cell proliferation drug, all CMT-3Ns except CMT-303 and CMT-308 had similar anti-cell proliferation activity (IC 50 : 2.5 -5.7 micro g/ml). IC 50 s for CMT-303 and CMT-308 were - 8.1 and -12.4 micro g/ml, respectively. Activity against tumor cell invasion was tested in vitro using the Matrigel invasion assay. All CMT-3Ns had similar anti- invasive activity. While cytotoxic activity of CMT-3 was strongly associated with cell death-effector caspase activation, mitochondrial permeablization and apoptosis, the CMT-3Ns weakly induced apoptosis and did not activate Caspase-3. However, the CMT-3Ns were able to induce mitochondrial permeabilization. This dichotomous mechanism of cytotoxic activity of CMTs may have significance in their selection for clinical application.
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Keywords: Chromatine fragmentation; capase activation; cell death assay; cell proliferation; culture conditioned medium; dedmethylamino tetracycline; depolarization of mitochondria; existing chemotherapeutics drugs; flow cytometry; metastatic drugs; modified tetracycluine; phoshatidyl serine; potent anti tumor; tumor cell invasio

Document Type: Review Article

Publication date: 2001-02-01

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