Cancer cells adapt FAM134B/BiP mediated ER-phagy to survive hypoxic stress.

In the tumor microenvironment, cancer cells experience hypoxia resulting in the accumulation of misfolded/unfolded proteins largely in the endoplasmic reticulum (ER). Consequently, ER proteotoxicity elicits unfolded protein response (UPR) as an adaptive mechanism to resolve ER stress. In addition to canonical UPR, proteotoxicity also stimulates the selective, autophagy-dependent, removal of discrete ER domains loaded with misfolded proteins to further alleviate ER stress. These mechanisms can favor cancer cell growth, metastasis, and long-term survival. Our investigations reveal that during hypoxia-induced ER stress, the ER-phagy receptor FAM134B targets damaged portions of ER into autophagosomes to restore ER homeostasis in cancer cells. Loss of FAM134B in breast cancer cells results in increased ER stress and reduced cell proliferation. Mechanistically, upon sensing hypoxia-induced proteotoxic stress, the ER chaperone BiP forms a complex with FAM134B and promotes ER-phagy. To prove the translational implication of our mechanistic findings, we identified vitexin as a pharmacological agent that disrupts FAM134B-BiP complex, inhibits ER-phagy, and potently suppresses breast cancer progression in vivo.

Anti-proliferative potential of phytochemical fractions isolated from Simarouba glauca DC leaf.

Emerging advancements in anticancer drug discovery research are leaning towards the plant-based bioactive fractions, which is a cocktail of naturally abundant two or more substances with unique proportions, exhibiting greater potential to combat cancers than the individual molecules. Thus, isolation and characterization of anti-cancer activity enriched fractions from plants is gaining scientific attention. Consistent with this view, one of the evidence-based traditional medicinal plants, well known for its anti-cancer potential, Simarouba glauca (SG) leaf has been scientifically examined to identify and isolate the potent anti-cancer fraction. The dried SG leaves were extracted successively with the solvents of increasing polarity. The phytochemical characterization of obtained extracts and fractions were carried out to determine the phenolic acid composition. All fractions were individually examined for anti-cancer property in cancer cells representing lungs, cervix, breast, colon and rectum in vitro. Among all fractions tested, the chloroform (SGC) and ethyl acetate (SGEA) extracts showed potent anti-proliferative effects by triggering apoptosis. In summary, our findings demonstrate that the extracts SGC and SGEA have potent anti-cancer activities compared to other fractions of SG leaf and thus warrant further pre-clinical studies to establish scientific basis for the anticancer potentials of SG.

Hypoxia Induced ER Stress Response as an Adaptive Mechanism in Cancer.

It is evident that regions within tumors are deprived of oxygen, which makes the microenvironment hypoxic. Cancer cells experiencing hypoxia undergo metabolic alterations and cytoprotective adaptive mechanisms to survive such stringent conditions. While such mechanisms provide potential therapeutic targets, the mechanisms by which hypoxia regulates adaptive responses-such as ER stress response, unfolded protein response (UPR), anti-oxidative responses, and autophagy-remain elusive. In this review, we summarize the complex interplay between hypoxia and the ER stress signaling pathways that are activated in the hypoxic microenvironment of the tumors.

Tricaproin Isolated From Simarouba glauca Inhibits the Growth of Human Colorectal Carcinoma Cell Lines by Targeting Class-1 Histone Deacetylases.

While anticancer properties of Simarouba glauca (SG, commonly known as Paradise tree) are well documented in ancient literature, the underlying mechanisms leading to cancer cell death begin to emerge very recently. The leaves of SG have been used as potential source of anticancer agents in traditional medicine. Recently attempts have been made to isolate anticancer agents from the leaves of SG using solvent extraction, which identified quassinoids as the molecules with tumoricidal activity. However, it is not known whether the anti-cancer potential of SG leaves is just because of quassinoids alone or any other phytochemicals also contribute for the potency of SG leaf extracts. Therefore, SG leaves were first extracted with hexane, chloroform, ethyl acetate, 70% ethanol, water and anti-cancer potential (for inhibiting colorectal cancer (CRC) cells HCT-116 and HCT-15 proliferation) determined using Sulforhodamine-B (SRB) assay. The chloroform fraction with maximal anticancer activity was further fractionated by activity-guided isolation procedure and structure of the most potent compound determined using spectral analysis. Analysis of the structural characterization data showed the presence of tricaproin (TCN). TCN inhibited CRC cells growth in a time- and dose dependent manner but not the normal cell line BEAS-2B. Mechanistically, TCN reduced oncogenic Class-I Histone deacetylases (HDACs) activity, followed by inducing apoptosis in cells. In conclusion, the anti-cancer potential of SG is in part due to the presence of TCN in the leaves.

Effect of crude extract of Eugenia jambolana Lam. on human cytochrome P450 enzymes.

The fruit of Eugenia jambolana Lam. is very popular for its anti-diabetic property. Previous studies on the crude extract of E. jambolana (EJE) have successfully explored the scientific basis for some of its traditional medicinal uses. Considering its wide use and consumption as a seasonal fruit, the present study investigates the ability of E. jambolana to interact with cytochrome P450 enzymes. The standardized EJE was incubated with pooled human liver microsomes to assess the CYP2C9-, CYP2D6-, and CYP3A4-mediated metabolism of diclofenac, dextromethorphan, and testosterone, respectively. The metabolites formed after the enzymatic reactions were quantified by high performance liquid chromatography. EJE showed differential effect on cytochrome P450 activities with an order of inhibitory potential as CYP2C9 > CYP3A4 > CYP2D6 having IC50 of 76.69, 359.02, and 493.05 µg/mL, respectively. The selectivity of EJE for CYP2C9 rather than CYP3A4 and CYP2D6 led to perform the enzyme kinetics to explicate the mechanism underlying the inhibition of CYP2C9-mediated diclofenac 4'-hydroxylation. EJE was notably potent in inhibiting the reaction in a non-competitive manner with Ki of 84.85 ± 5.27 µg/mL. The results revealed the CYP2C9 inhibitory potential of EJE with lower Ki value suggesting that EJE should be examined for its potential pharmacokinetic and pharmacodynamic interactions when concomitantly administered with other drugs.