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This study compared the antiproliferative effects of metformin and progesterone, via examination of the Bcl-2/Bax-caspase apoptotic pathway in estrogen-induced endometrial hyperplasia (EH) in 40 rats. Two rats died after bilateral oophorectomy, and 1 week after surgery, the remaining 38 were randomly divided into three groups: the first (control, n = 12) received 4 mg/kg 17β estradiol hemihydrate (E); the second (n = 13) received 4 mg/kg 17β estradiol hemihydrate and 50 mg/kg metformin (E + M); and the third (n = 13) received 4 mg/kg 17β estradiol hemihydrate and 1 mg/day medroxiprogesterone acetate (E + MPA). Histological markers and Bcl-2, Bax and caspase 9 expression were analyzed. Luminal epithelial thickness, density of gland and epithelial height was significantly higher in group E than in groups E + M and E + MPA. Histopathologic parameters were similar between the E + M and E + MPA groups. Bcl-2/Bax ratio was significantly decreased in the E + M and E + MPA groups and caspase 9 expression levels were significantly increased in the E + M and E + MPA groups, compared with the control group. In addition, Bcl-2/Bax ratio and caspase 9 expression were similar between the E + M and E + MPA groups. The data indicate that metformin reduces estrogen-induced EH in rats, via activation of the caspase-dependent mitochondrial apoptotic pathway, to the same degree as progesterone.

Interdisciplinary research has revolutionized the field of medicine and we have witnessed exponential increase in the high-impact research in past few decades. However, the road to this burgeoning research field is obstacle-ridden because of intratumor heterogeneity, loss of apoptosis and dysregulation of spatio-temporally controlled signaling pathways. Ground-breaking findings obtained through genetic, genomic and proteomic studies have considerably improved our concepts related to the complexity of protein network and excitingly, discovery of miRNAs has added another layer of intricacy to quantitatively regulated gene networks. In this review, we chronicle the milestone achievements and discuss how Pterostilbenes effectively regulated different cellular pathways. We have provided detailed mechanistic insights related to regulation of JAK-STAT signaling, Notch pathway, Wnt mediated intracellular signaling by pterostilbene. Underlying mechanisms about regulation of PI3K/AKT and MAPK pathways by pterostilbene in different cancers.  Regulation of Metastasis-associated protein 1 (MTA1) proteins and Human telomerase reverse transcriptase (hTERT) in cancer cells by pterostilbene. Pterostilbene has also been reported to modulate the expression of various oncogenic and tumor suppressor microRNAs in cancer cells. Better and sharper comprehension of the concepts associated with the modes of action of pterostilbene in different cancers will be useful in identification of cancers which can be efficiently targeted by pterostilbene.