Minocycline attenuates cardiac dysfunction in tumor-burdened mice

Abstract

Cardiovascular dysfunction as a result of tumor burden is becoming a recognized complication; however, the mechanisms remain unknown. A murine model of cancer cachexia has shown marked increases of matrix metalloproteinases (MMPs), known mediators of cardiac remodeling, in the left ventricle. The extent to which MMPs were involved in remodeling remained obscured. To this end a common antibiotic, minocycline, with MMP inhibitory properties was used to elucidate MMP involvement in tumor induced cardiovascular dysfunction. Tumor-bearing mice showed decreased cardiac function with reduced posterior wall thickness (PWTs) during systole, increased MMP and collagen expression consistent with fibrotic remodeling. Administration of minocycline preserved cardiac function in tumor bearing mice and decreased collagen RNA expression in the left ventricle. MMP protein levels were unaffected by minocycline administration, with the exception of MMP-9, indicating minocycline inhibition mechanisms are directly affecting MMP activity. Cancer induced cardiovascular dysfunction is an increasing concern, novel therapeutics are needed to prevent cardiac complications. Minocycline is a well-known antibiotic and recently has been shown to possess MMP inhibitory properties. Our findings presented here show that minocycline could represent a novel use for a long established drug in the prevention and treatment of cancer induced cardiovascular dysfunction.

Increased hypoxia-inducible factor-1α in striated muscle of tumor-bearing mice

“…In agreement with previous findings, we found depressed myocardial function in the hearts of tumor-bearing mice that reached significance at 19 days postinjection (7,41). This is most likely due to the LV wall being compromised, as evidenced by the reduction in PWTs.…”

Cardiac myocyte intrinsic contractility and calcium handling deficits underlie heart organ dysfunction in murine cancer cachexia

“…As tumor effects and cachexia effects on the heart are occurring simultaneously, it is difficult to isolate the independent effects of cachexia. However, previous work showed that a similar model using female mice bearing C26 tumors exhibited relatively little body weight loss and cardiac atrophy after 21 days with tumors 20 , 50 , 51 . Despite decreased fractional shortening in vivo, myocytes from these animals had no change in contraction amplitude compared to controls, and inconsistency between studies in the time required to complete a contraction/relaxation cycle.…”

Cardiac Cachexia: Unaddressed Aspect in Cancer Patients

“…A previous study revealed that dysregulated matrix metalloproteinases (MMPs) could contribute to detrimental molecular remodelling, resulting in cardiac abnormalities. A preclinical study conducted on 10-week-old CD2F1 female mice inoculated with C26 adenocarcinoma cells revealed that the administration of minocycline, an inhibitor of MMP, could improve cardiac function by restoring the contractility of cardiac myocytes and attenuating collagen I and III expression in the cardiac muscles [140]. Simvastatin (10 mg/kg/day once daily for 14 days), the inhibitor of the production of matrix metalloproteinase-9 and the drug of choice for dyslipidaemia, which is an important risk factor for cardiovascular disorders, was able to improve cardiac output (57.0 mL/min) in young Wister Han rats that had been injected with Yoshida AH-130 hepatoma cells compared to those who had been injected with a placebo (42.4 mL/min) and thus decreased the mortality rate (HR: 0.16, 95% CI: 0.04-0.76, p = 0.021) in the treated animals [141].…”