Disease Subtype–Independent Biomarkers of Breast Cancer Chemoprevention by the Ayurvedic Medicine Phytochemical Withaferin A

Samanta, Suman Kumar; Sehrawat, Anuradha; Kim, Su‐Hyeong; Hahm, Eun‐Ryeong; Shuai, Yongli; Roy, Ruchi; Pore, Subrata K.; Singh, Krishna B.; Christner, Susan M.; Beumer, Jan H.; Davidson, Nancy E.; Singh, Shivendra V.

doi:10.1093/jnci/djw293

Cited by 37 publications

(74 citation statements)

References 49 publications

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“…The peak plasma concentration of WA after intraperitoneal administration to mice (4 mg/kg body weight) was about 1.8 µM . We have also shown previously that WA is bioavailable in the mammary tumors of the rats . Hence, 2 µM WA concentration was used in most in vitro studies in this study.…”

Section: Resultsmentioning

confidence: 76%

“…The WA‐induced apoptotic cell death in human breast cancer cell lines was associated with the production of reactive oxygen species and accompanied by induction/activation of Bax and Bak proteins . The induction of Bak protein expression was also observed in vivo in chemically induced mammary tumors from WA‐treated rats in comparison with controls . Interestingly, normal mammary epithelial cells (MCF‐10A or HMEC) were shown to be markedly more resistant to cell‐cycle arrest and apoptosis induction by WA in comparison with breast cancer cells .…”

Section: Introductionmentioning

confidence: 95%

“…Breast cancer is a molecularly heterogeneous disease broadly grouped into different subtypes including luminal type, human epidermal growth factor receptor 2 (HER‐2)‐amplified, basal type, and normal‐like . Studies have shown in vivo chemopreventative efficacy of WA against two different subtypes of breast cancer in rodent models . In one such study, we showed that macroscopic mammary tumor size and microscopic mammary tumor area as well as the incidence of pulmonary metastasis were decreased significantly after 28 weeks of WA administration (0.1 mg/mouse, three times per week) to female mouse mammary tumor virus‐ neu (MMTV‐ neu ) transgenic mice, an animal model for HER‐2‐amplified breast cancer.…”

Section: Introductionmentioning

confidence: 99%

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Withaferin A inhibits expression of ataxia telangiectasia and Rad3‐related kinase and enhances sensitivity of human breast cancer cells to cisplatin

Hahm

Lee

Abella

et al. 2019

Molecular Carcinogenesis

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Ataxia telangiectasia and Rad3‐related (ATR) is a serine/threonine‐specific kinase that plays an important role in the maintenance of genomic integrity. In this study, we investigated the role of ATR in cell‐cycle arrest by withaferin A (WA), a cancer preventative steroidal lactone derived from Withania somnifera plant abundant in India and surrounding countries. The WA treatment decreased the viability of MCF‐7, MDA‐MB‐231, and SUM159 cells. Exposure of breast cancer cells to WA also resulted in suppression of protein level as well as phosphorylation of ATR and its downstream effector kinase (checkpoint kinase 1; CHK1). Both transcriptional and posttranscriptional mechanisms were involved in the WA‐mediated downregulation of ATR protein. Downregulation of ATR protein expression resulting from WA exposure was not attenuated by overexpression of manganese superoxide dismutase. In contrast, the overexpression of CHK1 attenuated WA‐mediated G2/M arrest and augmented S10 phosphorylation of histone H3, a marker of mitotic arrest. The protein level of ATR was lowered by about 50% in breast tumors of WA‐treated mouse mammary tumor virus‐neu mice when compared with vehicle‐treated controls but the difference was not significant due to small sample size. WA treatment sensitized MDA‐MB‐231 and SUM159 cells to growth inhibition and apoptosis induction by cisplatin. Cisplatin treatment resulted in increased autophosphorylation of ATR (T1989) and CHK1 (S345) phosphorylation that was markedly suppressed in the presence of WA. These results indicate that WA is an inhibitor of ATR in human breast cancer cells.

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Section: Resultsmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Withaferin A inhibits expression of ataxia telangiectasia and Rad3‐related kinase and enhances sensitivity of human breast cancer cells to cisplatin

Hahm

Lee

Abella

et al. 2019

Molecular Carcinogenesis

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“…The phenethyl isothiocyanate (PEITC) from cruciferous vegetables is another compound that has shown promising anticancer activity via downregulation of HER2, pSTAT3 and Bcl‐xL, and upregulation of Bim, Bax and caspase‐3 in BC cells . Withaferin‐A, an active compound from Withania Somnifera, induces mitotic arrest in tumors of MMTV‐ neu mice, decreases number and weight of tumors in N‐methyl‐N‐nitrosourea (NMU) induced rat BC model, decreases circulating leptin levels in rat plasma and downregulates transcription factor FoxQ1 and angiogenesis marker CD31 in treated tumors …”

Section: Determinants Of Bc Risk: Considerations For Bc Prevention Anmentioning

confidence: 99%

Translational opportunities for broad‐spectrum natural phytochemicals and targeted agent combinations in breast cancer

Nagaprashantha

Adhikari

Singhal

et al. 2017

Intl Journal of Cancer

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Breast cancer (BC) prevention and therapy in the context of life-style risk factors and biological drivers is a major focus of developmental therapeutics in oncology. Obesity, alcohol, chronic estrogen signaling and smoking have distinct BC precipitating and facilitating effects that may act alone or in combination. A spectrum of signaling events including enhanced oxidative stress and changes in estrogen-receptor (ER)-dependent and -independent signaling drive the progression of BC. Breast tumors modulate ERα/ERβ ratio, upregulate proliferative pathways driven by ERα and HER2 with a parallel loss and/or downregulation of tumor suppressors such as TP53 and PTEN which together impact the efficacy of therapeutic strategies and frequently lead to emergence of drug resistance. Natural phytochemicals modulate oxidative stress, leptin, integrin, HER2, MAPK, ERK, Wnt/β-catenin and NFκB signaling along with regulating ERα and ERβ, thereby presenting unique opportunities for both primary and combinatorial interventions in BC. In this regard, this article focuses on critical analyses of the evidence from multiple studies on the efficacy of natural phytochemicals in BC. In addition, areas in which the combinations of such effective natural phytochemicals with approved and/or developing anticancer agents can be translationally beneficial are discussed to derive evidence-based inference for addressing challenges in BC control and therapy.

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“…Cancer chemopreventive effect of WA has been demonstrated in preclinical rodent models of breast and other cancers . For example, the incidence of 7,12‐dimethylbenz[ a ]anthracene‐induced oral cancer in hamsters was completely inhibited by oral administration of 20 mg WA/kg body for 14 weeks .…”

Section: Introductionmentioning

confidence: 99%

Peptidyl‐prolyl cis/trans isomerase Pin1 regulates withaferin A‐mediated cell cycle arrest in human breast cancer cells

Samanta

Lee

Hahm

et al. 2018

Molecular Carcinogenesis

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We have reported previously that withaferin A (WA) prevents breast cancer development in mouse mammary tumor virus-neu (MMTV-neu) transgenic mice, but the mechanism is not fully understood. Unbiased proteomics of the mammary tumors from control- and WA-treated MMTV-neu mice revealed downregulation of peptidyl-prolyl cis/trans isomerase (Pin1) protein by WA administration. The present study extends these findings to elucidate the role of Pin1 in cancer chemopreventive mechanisms of WA. The mammary tumor level of Pin1 protein was lower by about 55% in WA-treated rats exposed to N-methyl-N-nitrosourea, compared to control. Exposure of MCF-7 and SK-BR-3 human breast cancer cells to WA resulted in downregulation of Pin1 protein. Ectopic expression of Pin1 attenuated G and/or mitotic arrest resulting from WA treatment in both MCF-7 and SK-BR-3 cells. WA-induced apoptosis was increased by Pin1 overexpression in MCF-7 cells but not in the SK-BR-3 cell line. In addition, molecular docking followed by mass spectrometry indicated covalent interaction of WA with cysteine 113 of Pin1. Overexpression of Pin1 mutant failed to attenuate WA-induced mitotic arrest or apoptosis in the MCF-7 cells. Furthermore, antibody array revealed upregulation of proapoptotic insulin-like growth factor binding proteins (IGFBPs), including IGFBP-3, IGFBP-4, IGFBP-5, and IGFBP-6, in Pin1 overexpressing MCF-7 cells following WA treatment when compared to empty vector transfected control cells. These data support a crucial role of the Pin1 for mitotic arrest and apoptosis signaling by WA at least in the MCF-7 cells.

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Disease Subtype–Independent Biomarkers of Breast Cancer Chemoprevention by the Ayurvedic Medicine Phytochemical Withaferin A

Abstract: WA is a promising chemopreventative phytochemical with the ability to inhibit at least two different subtypes of breast cancer.

Cited by 37 publications

References 49 publications

Withaferin A inhibits expression of ataxia telangiectasia and Rad3‐related kinase and enhances sensitivity of human breast cancer cells to cisplatin

Withaferin A inhibits expression of ataxia telangiectasia and Rad3‐related kinase and enhances sensitivity of human breast cancer cells to cisplatin

Translational opportunities for broad‐spectrum natural phytochemicals and targeted agent combinations in breast cancer

Peptidyl‐prolyl cis/trans isomerase Pin1 regulates withaferin A‐mediated cell cycle arrest in human breast cancer cells

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