Nimbolide epigenetically regulates autophagy and apoptosis in breast cancer

Pooladanda, Venkatesh; Bandi, Soumya; Mondi, Sandhya Rani; Gottumukkala, Krishna Mohan; Godugu, Chandraiah

doi:10.1016/j.tiv.2018.05.010

Cited by 48 publications

(32 citation statements)

References 35 publications

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“…Uncovering new therapeutic modalities in TNBCs would thus potentially contribute significantly to reducing breast cancer-associated mortalities. Consistent with previous reports showing anti-cancer activity in breast cancer cells, nimbolide impaired cell proliferation or serum-free cell survival in 231MFP and HCC38 TNBC cells ( Figure 1B, Figure S1) 14,15,17 . We also show that these effects on 231MFP and HCC38 viability are due to a significant increase in apoptotic cells with nimbolide treatment, assessed by flow cytometry analysis ( Figure 1C, Figure S1).…”

Section: Effects Of Nimbolide On Breast Cancer Cell Survival Prolifesupporting

confidence: 92%

“…Nimbolide has been shown to exert multiple therapeutic effects and possesses a cyclic enone capable of reacting with cysteines [10][11][12] . In the context of cancer, nimbolide has been shown to inhibit tumorigenesis and metastasis without causing any toxicity or unwanted side effects across a wide range of cancers 10,11,[13][14][15][16][17] . While previous studies suggest that nimbolide impairs cancer pathogenicity through modulating signaling pathways and transcription factors linked to survival, growth, invasion, angiogenesis, inflammation, and oxidative stress the direct targets of nimbolide still remain poorly characterized 10,15,[18][19][20][21][22] .…”

Section: Introductionmentioning

confidence: 99%

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Harnessing the Anti-Cancer Natural Product Nimbolide for Targeted Protein Degradation

Spradlin

Ward

et al. 2018

Preprint

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Nimbolide, a terpenoid natural product derived from the Neem tree, impairs cancer pathogenicity across many types of human cancers; however, the direct targets and mechanisms by which nimbolide exerts its effects are poorly understood. Here, we used activity-based protein profiling (ABPP) chemoproteomic platforms to discover that nimbolide reacts with a novel functional cysteine crucial for substrate recognition in the E3 ubiquitin ligase RNF114. Nimbolide impairs breast cancer cell proliferation in-part by disrupting RNF114 substrate recognition, leading to inhibition of ubiquitination and degradation of the tumor-suppressors such as p21, resulting in their rapid stabilization. We further demonstrate that nimbolide can be harnessed to recruit RNF114 as an E3 ligase in targeted protein degradation applications and show that synthetically simpler scaffolds are also capable of accessing this unique reactive site. Our study highlights the utility of ABPP platforms in uncovering unique druggable modalities accessed by natural products for cancer therapy and targeted protein degradation applications.

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Section: Effects Of Nimbolide On Breast Cancer Cell Survival Prolifesupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Harnessing the Anti-Cancer Natural Product Nimbolide for Targeted Protein Degradation

Spradlin

Ward

et al. 2018

Preprint

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“…The antigen–antibody complex was detected using HRP conjugated secondary antibodies, which were incubated with enhanced chemiluminescence detection solution and finally detected on Chemi‐Doc System (Vilber Lourmet, France). Similarly, nuclear proteins were isolated to study the expression of histone modifications in liver fibrosis as per a previous report …”

Section: Methodsmentioning

confidence: 99%

“…Similarly, nuclear proteins were isolated to study the expression of histone modifications in liver fibrosis as per a previous report. 35…”

Section: Western Blottingmentioning

confidence: 99%

Withaferin A reverses bile duct ligation‐induced liver fibrosis by modulating extracellular matrix deposition: Role of LOXL2/Snail1, vimentin, and NFκB signaling

et al. 2019

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Herein, we studied the effect of Withaferin A (WFA) in reversing bile duct ligation (BDL)‐induced liver fibrosis. BDL was performed on C57BL/6J mice and 2 days later, WFA (1 and 3 mg/kg) was administered for 12 days. Estimation of liver enzymes and assays for lipid peroxidation, reduced glutathione, and nitrite levels were performed. Picrosirius red, Masson's trichrome, and H&E staining were performed to study histological changes. WFA proved to be a holistic intervention for the attenuation and reversal of liver fibrosis. Reduction in inflammatory stimulus and oxidative stress restored the levels of stress‐related chaperone Hsp70 (p < .001 vs. BDL) in WFA treated groups. We found 3.59‐fold (p < .001) and 1.37‐fold (p < .01) reduction in the expression of lysyl oxidase like2 (LOXL2) and Snail1, respectively, in WFA‐treated animals as compared with BDL animals. These reductions led to 1.9‐fold (p < .001) elevation in levels of E‐cadherin signifying the reversal of epithelial to mesenchymal transition by WFA. Further, the reduction in LOXL2 levels enhanced the susceptibility of fibrotic scar toward degradation. The picrosirius red and Masson's trichrome staining done on liver tissue sections supported the above results. We, for the first time, report the role of WFA in modulating the expression of LOXL2 and Snail1 in addition to vimentin inhibition and regulation of NFκB signaling for the treatment of liver fibrosis.

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“…Effect of NCL on cell viability was determined by MTT assay as described earlier (Pooladanda, Bandi, Mondi, Gottumukkala, & Godugu, 2018). HaCaT and RAW 264.7 cells were seeded at a density of 3 × 10 3 /well in 96-well plates and treated with NCL at various concentrations.…”

Section: Cell Viabilitymentioning

confidence: 99%

Repurposing an old drug for new use: Niclosamide in psoriasis‐like skin inflammation

Thatikonda

Pooladanda

Godugu

2019

Journal Cellular Physiology

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Drug discovery is an onerous, extremely expensive, and time‐consuming process. Instead, drug repurposing is an attractive strategy for exploiting novel indications for a drug beyond its original use. The untapped potential of drug repurposing compensates the barriers associated with the drug discovery pipeline. Psoriasis is an autoimmune skin disease, where hyperproliferation of keratinocytes and exaggerated immune responses are the important hallmarks of the disease. Extensive in vitro and preclinical research has demonstrated that niclosamide was found to exert potent anticancer and anti‐inflammatory properties by targeting STAT3, p65 NF‐κB, and NFATc‐1 signaling paradigm with minimal host toxicity. From the disease perspective, the static intracellular molecular network in both cancer and psoriasis share overlapping pathological features in terms of hyperproliferation and chronic inflammation, which is mediated by the aforementioned signaling cascade. The plausible mechanistic relevance has prompted us to investigate the implementation of niclosamide for repositioning in psoriasis. Our in vitro and in vivo findings suggest that niclosamide inhibits keratinocytes hyperproliferation by reactive oxygen species‐mediated apoptosis through the loss of mitochondrial membrane potential, cell cycle arrest at Sub G1 phase, and DNA fragmentation. Furthermore, niclosamide treatment resulted in abrogation of lipopolysaccharide‐induced inflammatory cytokine levels in murine macrophages. Additionally, our results provided a preclinical rationale in imiquimod (IMQ)‐induced BALB/c mouse model, where niclosamide diligently mitigated the IMQ‐induced epidermal hyperplasia and inflammation by downregulating STAT3, p65 NF‐κB, and NFATc‐1 transcription factors along with Akt, Ki‐67, and ICAM‐1 protein expression.

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Nimbolide epigenetically regulates autophagy and apoptosis in breast cancer

Cited by 48 publications

References 35 publications

Harnessing the Anti-Cancer Natural Product Nimbolide for Targeted Protein Degradation

Harnessing the Anti-Cancer Natural Product Nimbolide for Targeted Protein Degradation

Withaferin A reverses bile duct ligation‐induced liver fibrosis by modulating extracellular matrix deposition: Role of LOXL2/Snail1, vimentin, and NFκB signaling

Repurposing an old drug for new use: Niclosamide in psoriasis‐like skin inflammation

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