Role of high-fat diet on the effect of pioglitazone and melatonin in a rat model of breast cancer

Abstract

The risk of cancer may be modulated by drugs with pleiotropic effects and diet has been implicated in the efficacy of treatment. The oncopreventive effects of the antidiabetic drug pioglitazone (PIO) and the anti-insomnia drug melatonin (MT), in vivo, have been proven before, but using a standard-type diet. This study evaluated the impact of a high-fat diet on their efficacy in chemically induced mammary carcinogenesis in Sprague-Dawley rats. Mammary tumours were induced by N-methyl-N-nitrosourea (50 mg/kg, intraperitoneal, on the 41st postnatal day). PIO and MT administration was initiated 11 days before the carcinogen application and lasted until the termination of the experiment at 16 weeks. PIO was administered in a diet (10% fat) at a concentration of 100 ppm and MT was administered in tap water (20 mg/l). PIO, MT and the combination did not significantly alter the basic tumour growth parameters. However, histopathology showed a decrease in the high-grade/low-grade tumour ratio, particularly in animals that received combined treatment (P<0.01). Semiquantitative immunohistochemistry indicated the proapoptotic effect of chemoprevention, particularly in the drug combination group (P<0.01), but no changes in tumour cell proliferation and angiogenesis were recorded. Results were evaluated by one-way analysis of variance or the Mann-Whitney U-test, respectively. PIO and MT, alone or in combination, administered to rats fed a high-fat diet reduced the proportion of high-grade tumours and promoted apoptosis in an in-vivo breast cancer model, although it did not suppress tumour growth. The impact of high dietary fat content on the chemopreventive efficacy of these and other substances should be considered in human studies.

Pioglitazone and breast cancer risk in female patients with type 2 diabetes mellitus: a retrospective cohort analysis

“…In an animal study, rosiglitazone suppresses mammary tumor growth in rats treated with the carcinogen 7,12-dimethylbenz(a)anthracene [ 20 ]. On the other hand, although pioglitazone inhibits aromatase expression by inhibiting proinflammatory prostaglandin E2 signaling and upregulating tumor-suppressor gene BRCA1 [ 21 ], it does not inhibit mammary tumor growth induced by N-methyl-N-nitrosourea in Sprague-Dawley rats fed a high-fat diet [ 22 ]. Studies also suggested that metformin and pioglitazone might have different effects on breast cancer cells.…”

Peroxisome proliferator-activated receptor gamma and BRCA1

“…In addition, pharmacological intervention is initiated at different time points relative to cancer initiation and study durations are mixed. Positive impacts provide support for the principle of PPARG agonist chemoprevention (Kocdor et al 2009, Li & Brown 2009, McCormick et al 2015, Ory et al 2018 but when significant effects are limited to hyperplasia and/or preneoplasia, alterations in cancer histology and/or mean tumor volume, there is less enthusiasm (Borbath et al 2007, Wu et al 2008, Skelhorne-Gross et al 2012, Nakles et al 2013, Bojková et al 2016, Alothman et al 2018. Occasional published studies report no effect at all (Yee et al 2005).…”

Melatonin May Increase Anticancer Potential of Pleiotropic Drugs

“…Although parameters of tumor growth were not significantly changed, pioglitazone alone decreased proportion of HG tumors and increased apoptosis in mammary cancer cells. MEL potentiated the effect of pioglitazone as evidenced by decrease in tumor frequency and further reduction in HG/LG ratio (Table S1, [325]).…”