Elimination of dysfunctional mitochondria through mitophagy suppresses benzo[a]pyrene-induced apoptosis.

Mitophagy, a special type of autophagy, plays an important role in the mitochondria quality control and cellular homeostasis. In this study, we examined the molecular mechanism of mitophagy induction with benzo[a]pyrene (B[a]P), a ubiquitous polycyclic aromatic hydrocarbon, which acts as a prosurvival response against apoptotic cell death. Our study showed that B[a]P displayed higher cytotoxicity in autophagy-deficient HaCaT cells as compared to control. Further, we showed that B[a]P triggered the Beclin-1-dependent autophagy through the mammalian target of rapamycin (mTOR)/AMP-activated protein kinase (AMPK) pathway. Moreover, our study indicated that the B[a]P-induced autophagy was initiated through the activation of cytochrome P450 1B1 (CYP1B1) and the aryl hydrocarbon receptor (AhR) in HaCaT cells. Intriguingly, the B[a]P-induced Beclin-1-mediated mitophagy was suppressed in CYP1B1 and AhR knockdown HaCaT cells, indicating a crucial role of B[a]P activation in the mitophagy induction to regulate cell death. B[a]P was shown to increase the mitochondrial dysfunction and decrease the mitochondrial membrane potential, resulting in depletion of ATP level along with the inhibition of the oxygen consumption rate in HaCaT cells. Importantly, the supplementation of methyl pyruvate compensated for the B[a]P-induced drop in the ATP level and mitigated the reactive oxygen species burden and autophagy. Mechanistically, B[a]P inhibited the manganese superoxide dismutase (MnSOD) activity and we found that the activated mitochondrial CYP1B1 interacted with MnSOD, inflicting mitophagy to protect from B[a]P-induced apoptosis. In summary, our study reveals mitophagy induction as a cellular protection mechanism against B[a]P-triggered toxicity and carcinogenesis.

Phytotherapeutic approach: a new hope for polycyclic aromatic hydrocarbons induced cellular disorders, autophagic and apoptotic cell death.

Polycyclic aromatic hydrocarbons (PAHs) comprise the major class of cancer-causing chemicals and are ranked ninth among the chemical compounds threatening to humans. Moreover, interest in PAHs has been mainly due to their genotoxic, teratogenic, mutagenic and carcinogenic property. Polymorphism in cytochrome P450 (CYP450) and aryl hydrocarbon receptor (AhR) has the capacity to convert procarcinogens into carcinogens, which is an imperative factor contributing to individual susceptibility to cancer development. The carcinogenicity potential of PAHs is related to their ability to bind to DNA, thereby enhances DNA cross-linking, causing a series of disruptive effects which can result in tumor initiation. They induce cellular toxicity by regulating the generation of reactive oxygen species (ROS), which arbitrate apoptosis. Additionally, cellular toxicity-mediated apoptotic and autophagic cell death and immune suppression by industrial pollutants PAH, provide fertile ground for the proliferation of mutated cells, which results in cancer growth and progression. PAHs play a foremost role in angiogenesis necessary for tumor metastasization by promoting the upregulation of metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF) and hypoxia inducible factor (HIF) in human cancer cells. This review sheds light on the molecular mechanisms of PAHs induced cancer development as well as autophagic and apoptotic cell death. Besides that authors have unraveled how phytotherapeutics is an alternate potential therapeutics acting as a savior from the toxic effects of PAHs for safer and cost effective perspectives.

Bacopa monnieri-Induced Protective Autophagy Inhibits Benzo[a]pyrene-Mediated Apoptosis.

Benzo[a]pyrene (B[a]P) is capable of inducing oxidative stress and cellular injuries leading to cell death and associates with a significant risk of cancer development. Prevention of B[a]P-induced cellular toxicity with herbal compound through regulation of mitochondrial oxidative stress might protect cell death and have therapeutic benefit to human health. In this study, we demonstrated the cytoprotective role of Bacopa monnieri (BM) against B[a]P-induced apoptosis through autophagy induction. Pretreatment with BM rescued the reduction in cell viability in B[a]P-treated human keratinocytes (HaCaT) cells indicating the cytoprotective potential of BM against B[a]P. Moreover, BM was found to inhibit B[a]P-mediated reactive oxygen species (ROS)-induced apoptosis activation in HaCaT cells. Furthermore, BM was found to preserve mitochondrial membrane potential and inhibited release of cytochrome c in B[a]P-treated HaCaT cells. Bacopa monnieri induced protective autophagy; we knocked down Beclin-1, and data showed that BM was unable to protect from B[a]P-induced mitochondrial ROS-mediated apoptosis in Beclin-1-deficient HaCaT cells. Moreover, we established that B[a]P-induced damaged mitochondria were found to colocalize and degraded within autolysosomes in order to protect HaCaT cells from mitochondrial injury. In conclusion, B[a]P-induced apoptosis was rescued by BM treatment and provided cytoprotection through Beclin-1-dependent autophagy activation. Copyright © 2016 John Wiley & Sons, Ltd.

Abrus agglutinin suppresses human hepatocellular carcinoma in vitro and in vivo by inducing caspase-mediated cell death.

AIM: Abrus agglutinin (AGG) from the seeds of Indian medicinal plant Abrus precatorius belongs to the class II ribosome inactivating protein family. In this study we investigated the anticancer effects of AGG against human hepatocellular carcinoma in vitro and in vivo. METHODS: Cell proliferation, DNA fragmentation, Annexin V binding, immunocytofluorescence, Western blotting, caspase activity assays and luciferase assays were performed to evaluate AGG in human liver cancer cells HepG2. Immunohistochemical staining and TUNEL expression were studied in tumor samples of HepG2-xenografted nude mice. RESULTS: AGG induced apoptosis in HepG2 cells in a dose- and time-dependent manner. AGG-treated HepG2 cells demonstrated an increase in caspase 3/7, 8 and 9 activities and a sharp decrease in the Bcl-2/Bax ratio, indicating activation of a caspase cascade. Co-treatment of HepG2 cells with AGG and a caspase inhibitor or treatment of AGG in Bax knockout HepG2 cells decreased the caspase 3/7 activity in comparison to HepG2 cells exposed only to AGG. Moreover, AGG decreased the expression of Hsp90 and suppressed Akt phosphorylation and NF-κB expression in HepG2 cells. Finally, AGG treatment significantly reduced tumor growth in nude mice bearing HepG2 xenografts, increased TUNEL expression and decreased CD-31 and Ki-67 expression compared to levels observed in the untreated control mice bearing HepG2 cells. CONCLUSION: AGG inhibits the growth and progression of HepG2 cells by inducing caspase-mediated cell death. The agglutinin could be an alternative natural remedy for the treatment of human hepatocellular carcinomas.