Quercetin-6-C-β-d-glucopyranoside, natural analog of quercetin exhibits anti-prostate cancer activity by inhibiting Akt-mTOR pathway via aryl hydrocarbon receptor

Ullah, H.; Kumar, Rajeev; Saini, Karan Singh; Kumar, Amit; Kumar, Sudhir; Ramakrishna, E.; Maurya, Rakesh; Konwar, Rituraj; Chattopadhyay, Naibedya

doi:10.1016/j.biochi.2015.10.012

Cited by 42 publications

(17 citation statements)

References 76 publications

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“…Among the amino acids, kynurenine is a natural ligand of the aryl hydrocarbon receptor (AhR) . Activation of mTORC1 by kynurenine is consistent with the concept of a regulatory cross‐talk occurring between the AhR and mTOR pathways . Whereas the levels of kynurenine and its precursor, tryptophan, are increased, the levels of cysteine, histidine, glutamine, and glutamate are depleted in patients with SLE .…”

Section: Effect Of Nutrients On Autoimmune Rheumatic Diseasessupporting

confidence: 59%

Review: Metabolic Control of Immune System Activation in Rheumatic Diseases

Perl

2017

Arthritis & Rheumatology

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Metabolic pathways mediate lineage specification within the immune system through the regulation of glucose utilization, a process that generates energy in the form of ATP and synthesis of amino acids, nucleotides, and lipids to enable cell growth, proliferation, and survival. CD4+ T cells, a proinflammatory cell subset, preferentially produce ATP through glycolysis, whereas cells with an antiinflammatory lineage, such as memory and regulatory T cells, favor mitochondrial ATP generation. In conditions of metabolic stress or a shortage of nutrients, cells rely on autophagy to secure amino acids and other substrates, while survival depends on the sparing of mitochondria and maintenance of a reducing environment. The pentose phosphate pathway acts as a key gatekeeper of inflammation by supplying ribose‐5‐phosphate for cell proliferation and NADPH for antioxidant defenses. Increased lysosomal catabolism, accumulation of branched amino acids, glutamine, kynurenine, and histidine, and depletion of glutathione and cysteine activate the mechanistic target of rapamycin (mTOR), an arbiter of lineage development within the innate and adaptive immune systems. Mapping the impact of susceptibility genes to metabolic pathways allows for better understanding and therapeutic targeting of disease‐specific expansion of proinflammatory cells. Therapeutic approaches aimed at glutathione depletion and mTOR pathway activation appear to be safe and effective for treating lupus, while an opposing intervention may be of benefit in rheumatoid arthritis. Environmental sources of origin for metabolites within immune cells may include microbiota and plants. Thus, a better understanding of the pathways of immunometabolism could provide new insights into the pathogenesis and treatment of the rheumatic diseases.

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Section: Effect Of Nutrients On Autoimmune Rheumatic Diseasessupporting

confidence: 59%

Review: Metabolic Control of Immune System Activation in Rheumatic Diseases

Perl

2017

Arthritis & Rheumatology

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“…These limitations can be overcome by the use of quercetin-containing nanomicelles, which have been shown to increase the bioavailability of quercetin and inhibit the growth of PC-3 prostate cancer xenografts (41). Similarly, a naturally occurring cis-glycoside of quercetin, quercetin-6-C-b-D-glucopyranoside with better bioavailability was isolated from the bark of Ulmus wallichiana (42). Thus, identification of quercetin analogs with higher bioavailability and improved anti-cancer activity may be an attractive option.…”

Section: Discussionmentioning

confidence: 99%

Quercetin Targets hnRNPA1 to Overcome Enzalutamide Resistance in Prostate Cancer Cells

Tummala

Lou

Gao

et al. 2017

Molecular Cancer Therapeutics

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Prostate cancer remains dependent on androgen receptor signaling even after castration. Aberrant androgen receptor signaling in castration resistant prostate cancer is mediated by mechanisms such as alterations in the androgen receptor and activation of interacting signaling pathways. Clinical evidence confirms that resistance to the next generation anti-androgen, enzalutamide, may be mediated to a large extent by alternative splicing of the androgen receptor to generate constitutively active splice variants such as AR-V7. The splice variants AR-V7 and Arv567es have been implicated in the resistance to not only enzalutamide, but also to abiraterone and other conventional therapeutics such as taxanes. Numerous studies including ours suggest that splicing factors such as hnRNPA1 promote the generation of AR-V7, thus contributing to enzalutamide resistance in prostate cancer cells. In the present study, we discovered that quercetin, a naturally occurring polyphenolic compound, reduces the expression of hnRNPA1, and consequently, that of AR-V7. The suppression of AR-V7 by quercetin resensitizes enzalutamide-resistant prostate cancer cells to treatment with enzalutamide. Our results indicate that quercetin downregulates hnRNPA1 expression, downregulates the expression of AR-V7, antagonizes androgen receptor signaling, and resensitizes enzalutamide-resistant prostate cancer cells to enzalutamide treatment in vivo in mouse xenografts. These findings demonstrate that suppressing the alternative splicing of the androgen receptor may have important implications in overcoming the resistance to next-generation anti-androgen therapy.

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“…The effect of CT-1 on the cell cycle distribution in MCF-7 and LA-7 cells was determined using PI staining followed by flow cytometry [26]. Briefly, 1 Â 10 5 cells were seeded in culture flask and allowed to grow for 24 h. Cells was treated with different concentration of CT-1 for 24 h. At the end of incubation, cells were harvested, fixed with 70% ethanol for 1 h at 48C, washed with PBS and incubated with 30 mg/sample of PI and 30 mg/sample RNase for 30 min at room temperature.…”

Section: Cell Cycle Analysismentioning

confidence: 99%

New orally active DNA minor groove binding small molecule CT‐1 acts against breast cancer by targeting tumor DNA damage leading to p53‐dependent apoptosis

Saini

Ullah

Ashraf

et al. 2016

Molecular Carcinogenesis

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Targeting tumor DNA damage and p53 pathway is a clinically established strategy in the development of cancer chemotherapeutics. Majority of anti-cancer drugs are delivered through parenteral route for reasons like severe toxicity, lack of stability, and poor enteral absorption. Current DNA targeting drugs in clinical like anthracycline suffers from major drawbacks like cardiotoxicity. Here, we report identification of a new orally active small molecule curcumin-triazole conjugate (CT-1) with significant anti-breast cancer activity in vitro and in vivo. CT-1 selectively and significantly inhibits viability of breast cancer cell lines; retards cells cycle progression at S phase and induce mitochondrial-mediated cell apoptosis. CT-1 selectively binds to minor groove of DNA and induces DNA damage leading to increase in p53 along with decrease in its ubiquitination. Inhibition of p53 with pharmacological inhibitor as well as siRNA revealed the necessity of p53 in CT-1-mediated anti-cancer effects in breast cancer cells. Studies using several other intact p53 and deficient p53 cancer cell lines further confirmed necessity of p53 in CT-1-mediated anti-cancer response. Pharmacological inhibition of pan-caspase showed CT-1 induces caspase-dependent cell death in breast cancer cells. Most interestingly, oral administration of CT-1 induces significant inhibition of tumor growth in LA-7 syngeneic orthotropic rat mammary tumor model. CT-1 treated mammary tumor shows enhancement in DNA damage, p53 upregulation, and apoptosis. Collectively, CT-1 exhibits potent anti-cancer effect both in vitro and in vivo and could serve as a safe orally active lead for anti-cancer drug development. © 2016 Wiley Periodicals, Inc.

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Quercetin-6-C-β-d-glucopyranoside, natural analog of quercetin exhibits anti-prostate cancer activity by inhibiting Akt-mTOR pathway via aryl hydrocarbon receptor

Cited by 42 publications

References 76 publications

Review: Metabolic Control of Immune System Activation in Rheumatic Diseases

Review: Metabolic Control of Immune System Activation in Rheumatic Diseases

Quercetin Targets hnRNPA1 to Overcome Enzalutamide Resistance in Prostate Cancer Cells

New orally active DNA minor groove binding small molecule CT‐1 acts against breast cancer by targeting tumor DNA damage leading to p53‐dependent apoptosis

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