Chemically modified non-antimicrobial tetracyclines are multifunctional drugs against advanced cancers☆

Abstract

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 (CMT, 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.

Percutaneous Doxycycline Treatment of Aneurysmal Bone Cysts With Low Recurrence Rate: A Preliminary Report

“…Furthermore, the lack of need for posttreatment physical rehabilitation (once pathologic fractures heal) offers patients greater mobility and maintenance of normal activities of daily living (recreational and work activity within limits set by the patient's orthopaedic surgeon) during the therapeutic regimen. Although the exact mechanism of regression is not known, pathology results in three patients not completing the full protocol of percutaneous treatment suggest direct cytotoxic action on the mesenchymal tumoral ABC component in addition to known metabolic therapeutic targets of doxycycline that inhibit VEGF, MMP, and osteoclast function [4,5,7,12,13,15,18,19,24,27,43].…”

“…In addition to a radiographic demonstration of tumor involution and bony healing, a pathologic analysis of three operative tissue specimens at the authors' institution, after percutaneous doxycycline treatment, documented the direct cytotoxic effect of doxycycline on the mesenchymal ABC cells. Beyond simple cytotoxicity, doxycycline is antiangiogenic [18,37], a potent inhibitor of MMP [12,13,27], an inhibitor of osteoclastic activity [12,13], induces apoptosis in osteoclasts, and promotes osteoblastic activity [4,7,12,13,15,19]. These multiple sites of action serve well to target the neoplastic cell of an ABC, destructive osteoclasts, tumor vascularity ingrowth, and support osteoblastic healing after tumor ablation.…”

Doxycycline down-regulates matrix metalloproteinase expression and inhibits NF-κB signaling in LPS-induced PC3 cells

“…Prostate cancer is the third cause of cancer-associated death in men after lung cancer in developed countries [1][2][3]. Although early detection of prostate cancer is crucial, several biomarkers for early screening are still controversial [4,5].…”

“…Although early detection of prostate cancer is crucial, several biomarkers for early screening are still controversial [4,5]. Over 70% of the patients are cured after various primary treatment options such as surgery, radiotherapy and androgen-deprivation therapy [2,6]. However, recurrence which occurs in 34% of the patients within 5 years and in 46% of the patients after 10 years limits management of the disease and prevents better cancer control and lower morbidity [2,6].…”

Studies on antitumor activity spectrum of doxycycline

“…[6] As a semi-synthetic tetracycline, doxycycline inhibits matrix metalloproteinase (MMP) activation, prevents cell proliferation, and downregulates DNA-dependent protein kinase. [7,8] …”