Melatonin potentiates the anti‐tumour effect of pravastatin in rat mammary gland carcinoma model

Abstract

Previous studies in the field of cancer research have suggested a possible role for statins in the reduction of risk in certain malignancies. The purpose of these studies was to examine the chemopreventive effects of pravastatin alone and in combination with pineal hormone melatonin in the N-methyl-N-nitrosourea-induced mammary carcinogenesis model. Pravastatin was given orally (1 00 mg/kg) and melatonin was added to the water (20 μg/ml). Chemoprevention began seven days prior to carcinogen administration and subsequently continued for 15 weeks until autopsy. At autopsy, mammary tumours were removed and prepared for histopathological and immunohistochemical analysis. Parameters of experimental carcinogenesis, mechanism of action (biomarkers of apoptosis, angiogenesis and proliferation) and side effects after long-term treatment in animals were assessed. Pravastatin alone suppressed tumour frequency by 20.5% and average tumour volume by 15% compared with controls. Combined administration of the drugs decreased tumour frequency by 69% and lengthened tumour latency by nine days compared with control animals. The ration between high and low grade carcinomas was apparently reduced in both treated groups. The analysis of carcinoma cells showed significant expression increase in caspase-3 and caspase-7 after pravastatin treatment; however, combined treatment even more pronounced increase in the expression of both caspases. Regarding VEGFR-2 expression, a small effect in carcinomas of both treated groups was found. In plasma metabolism evaluation, pravastatin alone significantly decreased levels of glucose and triacylglycerols. Our results suggest a mild anti-neoplastic effect of pravastatin in this rat mammary gland carcinoma model. Statins co-administered with other suitable drug (e.g. melatonin) should be further evaluated for tumour-preventive properties.

Melatonin and IL‐25 modulate apoptosis and angiogenesis mediators in metastatic (CF‐41) and non‐metastatic (CMT‐U229) canine mammary tumour cells

“…Another study by El‐Aziz et al reported a significant increase in caspase‐3 activity and DNA fragmentation in breast cancer‐bearing rats treated with melatonin in association with other agents. In another animal study, melatonin in combination with pravastatin noticeable enhanced expression of both caspase‐3 and caspase‐7 in rat mammary carcinoma cells in comparison with pravastatin alone . These results are in contrast with those of Kepka et al, where melatonin was shown to significantly reduce the early and late apoptosis of peritoneal leucocytes, by specifically inhibiting the extrinsic apoptosis pathway.…”

“…A large number of studies support the role of melatonin in the developmental and cellular processes, such as haematopoiesis and oxidative damage, while others indicate therapeutic potential, based on demonstrated anti‐angiogenic, anti‐inflammatory, anti‐cachectic, pro‐apoptotic,, immune‐stimulatory, and metabolism‐modulatory activities . In addition, melatonin can potentiate the anti‐tumour effects of other drugs . Although various studies demonstrated a clear anti‐cancer effect of melatonin, it cannot alone cause a complete regression of tumour, indicating the need to identify strategies whereby melatonin could act synergistically (or additively) to potentiate the anti‐cancer effects of other agents.…”

Melatonin as an antioxidant: under promises but over delivers

“…Statins reportedly have additional benefits including oncostatic actions and antifibrillating and defibrillating potential. Melatonin was found to exaggerate the cancer‐inhibiting actions of pitavastatin and pravastatin against breast cancer in experimental studies. Melatonin also has antiarrhythmic potential equivalent to that of atorvastatin in an isolated heart model .…”

Melatonin and endoplasmic reticulum stress: relation to autophagy and apoptosis

“…The major obstacle in cancer treatments is the resistance acquired by carcinoma cells against current chemotherapy drugs, and there are increasing evidence that ER stress is activated in various solid tumors favoring in part this resistance . There are studies where melatonin acts as a potent therapeutic agent in combination with other drugs to support the efficacy of anticancer agents . Furthermore, disturbances in melatonin production have been reported to drive resistance to tamoxifen .…”