Elucidating Mechanisms of Benzo[a]pyrene Mediated Apoptotic and Autophagic Cell Death and its Prevention with Phytotherapeutics

Polycyclic aromatic hydrocarbons form an active source of air pollution that affects our health and environment. In this study, we deciphered the role of benzo[a]pyrene (B[a]P) on cellular mechanism associated cell death. The particulate matter collected from an industrial area of Rourkela city found to have B[a]P and other unidentified environmental pollutants that had mutagenic and proapoptotic activity. The apoptotic potential of B[a]P was supported by ligand-protein and protein-protein interaction in silico which was validated on human keratinocyte (HaCaT) cell line. Our prediction showed that B[a]P was activated by cytochrome P450 (CYP1B1) to induce multiple cellular effects related to activation of the aryl hydrocarbon receptor (AhR) due to formation of toxic metabolites and this in turn activated caspases. Further, we showed that B[a]P induced mitochondrial mediated autophagy dependent cell death through the canonical pathway in HaCaT cells. The autophagic cell death induced by B[a]P was found to be mediated through AMPK/mTOR pathway. We showed that B[a]P abrogated ATP generation and activated reactive oxygen production to induce toxic mitophagy in HaCaT cells. In addition, we identified Bacopa monneiri (BM) plant extract as an inducer of protective autophagy, which may directly contribute to the antioxidant promoting potential of BM on B[a]P induced cell death through Beclin-1 dependent autophagy activation. The present study provided deep insight into the mechanism of B[a]P-mediated cellular toxicity and elucidated the further scope for the development of phytotherapeutics against environmental air pollutants

Reproductive factors and breast cancer risk: A meta-analysis of case–control studies in Indian women

Background/Objective: India is the world's most biodiverse region and is undergoing a period of dramatic social and economic change. Due to population's explosion, climate change and lax implementation of environmental policies, the incidence of breast cancer is increasing. From population-based cancer registry data, breast cancer is the most common cancer in women in urban registries where it constitutes more than 30% of all cancers in females. We conducted a meta-analysis of all breast cancer case–control studies conducted in India during 1991–2018 to find pooled estimates of odds ratio (OR). Materials and Methods: Eligible studies were identified through a comprehensive literature search of PubMed, EMBASE, and HINARI databases from 1991 to January 2018. This analysis included 24 observational studies out of 34 that reported the case–control distribution of reproductive factors, body mass index (BMI) and type of residence. The analysis was performed using RevMan 5.3 (Review Manager, 2017) applying the random-effects model. Results: A total of 21,511 patients (9889 cases and 11,622 controls) were analyzed, resulting in statistically significant association between breast cancer and the following reproductive factors: never breastfeed (OR: 3.69; 95% confidence interval [CI]: 1.70, 8.01), menopausal age >50 years (OR: 2.88; 95% CI: 1.85, 3.85), menarche age 25 years (OR: 1.57; 95% CI: 1.37, 1.80). Family history (FH) of breast cancer (OR: 5.33; 95% CI: 2.89, 9.82), obesity (OR: 1.19; 95% CI: 1.00, 1.42), and urban residence (OR: 1.22; 95% CI: 1.03, 1.44) were also found to be significant risk factors. Conclusion: The results of this meta-analysis are indicative of significant associations between reproductive factors and breast cancer risk, profoundly so among women experiencing menopause after the age of 50, women who never breastfeed and FH of breast cancer

Abrus Agglutinin, a type II ribosome inactivating protein inhibits Akt/PH domain to induce endoplasmic reticulum stress mediated autophagy-dependent cell death

Abrus agglutinin (AGG), a type II ribosome-inactivating protein has been found to induce mitochondrial apoptosis. In the present study, we documented that AGG-mediated Akt dephosphorylation led to ER stress resulting the induction of autophagy-dependent cell death through the canonical pathway in cervical cancer cells. Inhibition of autophagic death with 3-methyladenine (3-MA) and siRNA of Beclin-1 and ATG5 increased AGG-induced apoptosis. Further, inhibiting apoptosis by Z-DEVD-FMK and N-acetyl cysteine (NAC) increased autophagic cell death after AGG treatment, suggesting that AGG simultaneously induced autophagic and apoptotic death in HeLa cells. Additionally, it observed that AGG-induced autophagic cell death in Bax knock down (Bax-KD) and 5-FU resistant HeLa cells, confirming as an alternate cell killing pathway to apoptosis. At the molecular level, AGG-induced ER stress in PERK dependent pathway and inhibition of ER stress by salubrinal, eIF2 phosphatase inhibitor as well as siPERK reduced autophagic death in the presence of AGG. Further, our in silico and colocalization study showed that AGG interacted with pleckstrin homology (PH) domain of Akt to suppress its phosphorylation and consequent downstream mTOR dephosphorylation in HeLa cells. We showed that Akt overexpression could not augment GRP78 expression and reduced autophagic cell death by AGG as compared to pcDNA control, indicating Akt modulation was the upstream signal during AGG's ER stress mediated autophagic cell death. In conclusion, we established that AGG stimulated cell death by autophagy might be used as an alternative tumor suppressor mechanism in human cervical cancer. (c) 2016 Wiley Periodicals, Inc

Autophagy: cancer’s friend or foe?

The functional relevance of autophagy in tumor formation and progression remains controversial. Autophagy can promote tumor suppression during cancer initiation and protect tumors during progression. Autophagy-associated cell death may act as a tumor suppressor, with several autophagy-related genes deleted in cancers. Loss of autophagy induces genomic instability and necrosis with inflammation in mouse tumor models. Conversely, autophagy enhances survival of tumor cells subjected to metabolic stress and may promote metastasis by enhancing tumor cell survival under environmental stress. Unraveling the complex molecular regulation and multiple diverse roles of autophagy is pivotal in guiding development of rational and novel cancer therapies

Abrus agglutinin is a potent anti-proliferative and anti-angiogenic agent in human breast cancer

Abrus agglutinin (AGG), a plant lectin isolated from the seeds of Abrus precatorius, has documented antitumor and immunostimulatory effects in murine models. To examine possible antitumor activity against breast cancer, we established human breast tumor xenografts in athymic nude mice and intraperitoneally administered AGG. AGG inhibited tumor growth and angiogenesis as confirmed by monitoring the expression of Ki‐67 and CD‐31, respectively. In addition, TUNEL positive cells increased in breast tumors treated with AGG suggesting that AGG mediates anti‐tumorigenic activity through induction of apoptosis and inhibition of angiogenesis. On a molecular level, AGG caused extrinsic apoptosis through ROS generation that was AKT‐dependent in breast cancer cells, without affecting primary mammary epithelial cells, suggesting potential cancer specificity of this natural compound. In addition, using HUVECs, AGG inhibited expression of the pro‐angiogenic factor IGFBP‐2 in an AKT‐dependent manner, reducing angiogenic phenotypes both in vitro and in vivo. Overall, the present results establish that AGG promotes both apoptosis and anti‐angiogenic activities in human breast tumor cells, which might be exploited for treatment of breast and other cancers