Innovative Strategy for the Prevention and Treatment of Metastatic Prostate Cancer: Modified Tetracyclines as Chemotherapeutics

摘要

The overall goal of this funded project is to determine the utility of non-antibiotic forms of chemically modified tetracycline (CMT) against metastatic prostate cancer, with specific emphasis on prostate cancer-metastasis to bone. During the first phase of this project after screening about 10 analogues of CMTs, we identified a non-antimicrobial CMT, 6-deoxy, 6-demethyl, 4- -dedimethylamino tetracycline (CMT-3, COL-3) as a potent orally bioavailable anti-neoplastic and anti-metastatic agent. Although we had initially hypothesized OMTs as anti-metastatic agents due to their strong anti- metalloproteinase (anti-collagenase) activity in several systems 1-3, we discovered some of the CMTs have activities similar to cytotoxic chemotherapeutic agents. We found, CMTs inhibit cell proliferation via mitochondrial permeabilization, induction of apoptosis and by arresting cells at GlIS boundary 46. These properties combined with their strong affinity for bone matrix led us to test the efficacy of CMT-3 on bone metastasis. We reported that when tested on a highly aggressive prostate cancer model, induced to form skeletalilumbar bone metastasis, CMT-3 was able to inhibit development of paraplegia and cause a significant delay in development of morbidity associated with lung metastasis .