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Autophagy, a regulated nutrient recycling program can affect both cell survival and cell death. Here, we show that Ormeloxifene (ORM), a selective estrogen receptor modulator approved for oral contraceptive use induces autophagic flux in ovarian cancer cells, which is activated by an ER stress response upstream of autophagy. The ER stress response is characterized by activation of IRE1α, PERK and ATF6 and is under regulation of JNK. Pharmacological inhibition of either autophagy or ER stress increased cell survival, as did silencing of autophagy proteins LC3 and Beclin 1, implying that ORM-induced autophagy is pro-death in nature. Ultrastructural observations of treated cells confirmed stages of autophagic maturation. Caspase-dependent apoptosis succeeded these events and was characterized by generation of reactive oxygen species and disruption of mitochondrial membrane potential. A concomitant inhibition of the Akt/mTOR axis was also observed with possible regulation of Akt by ORM. ORM inhibited tumor growth in ovarian xenograft model and displayed autophagic activity. In summary, in vitro and in vivo results reveal that ORM induces autophagy-associated cell death to attenuate proliferation of ovarian cancer cells. Our results demonstrate that using ORM in combination with ER stress and autophagy modulators could offer better therapeutic outcome in ovarian cancer.

Different alkyl amide (15a-l) and alkyl amine (16a-e) derivatives of 7,8-dimethoxy-3-hydroxy-2-(4-methoxyphenyl)benzopyran-4-one were synthesized and evaluated for their anticancer activity against five different cancer cell lines using SRB assay. Compounds 15e, 15i, 15j and 16a-e showed significant anticancer activity within the range of IC 50 2.58-34.86μM. The most promising molecule, 16c, was further analyzed for its effect on cell cycle and apoptosis of estrogen receptor positive cancer cells (MCF-7 cells) which showed that 16c triggered apoptosis in MCF-7 cells and arrested cells population at sub-G 0 (apoptotic) and G 2 M phase. In tubulin polymerization assay, 16c interfered with kinetics of tubulin polymerization., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Development of target oriented chemotherapeutics for treatment of chronic diseases have been considered as an important approach in drug development. Following this approach, in our efforts for exploration of new osteogenic leads, substituted 3-aryl-2H-benzopyran and 3-aryl-3H-benzopyran derivatives (19, 20a-e, 21, 22a-e, 26, 27, 28a-e, 29, 31a-b, 32 and 33) have been characterized as estrogen receptor-β selective osteogenic (bone forming) agents. The synthesized compounds were evaluated for osteogenic activity using mouse calvarial osteoblast cells. Four compounds viz20b, 22a, 27and 32 showed significant osteogenic activity at EC50 values 1.35, 34.5, 407 and 29.5pM respectively. Out of these, 20b and 32 were analyzed for their bone mineralization efficacy and osteogenic gene expression by qPCR. The results showed that 20b and 32 significantly increased mineral nodule formation and the transcript levels of BMP-2, RUNX-2 and osteocalcin at 100pM concentrations respectively. Further mechanistic studies of 20b and 32 using transiently knocked down expression of ER-α and β in mouse osteoblast (MOBs) showed that 20b and 32 exerts osteogenic efficacy via activation of estrogen receptor-β preferentially. Additionally, compounds showed significant anticancer activity in a panel of cancer cell lines within the range of (IC50) 6.54-27.79μM. The most active molecule, 22b inhibited proliferation of cells by inducing apoptosis and arresting cell cycle at sub-G0 phase with concomitant decrease in cells at S phase., (Copyright © 2016 Elsevier Ltd. All rights reserved.)