Metabolomics Reveals that Dietary Xenoestrogens Alter Cellular Metabolism Induced by Palbociclib/Letrozole Combination Cancer Therapy

Warth, Benedikt; Raffeiner, Philipp; Granados, A.L. Ortega; Huan, Tao; Fang, Mingliang; Forsberg, Erica M.; Benton, H. Paul; Goetz, Laura H.; Johnson, Caroline H.; Siuzdak, Gary

doi:10.1016/j.chembiol.2017.12.010

Cited by 56 publications

(41 citation statements)

References 53 publications

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“…Dosing schedules, with correlative pharmacodynamics that avoid potential feedback mechanisms, warrant further investigation.Selective CDK4/6 inhibitors together with other targeted agents or chemotherapy are also being investigated in the setting of advanced cancers 13,14. Although combination therapy has yielded better results in clinical studies performed to date, identifying the most promising and best-tolerated CDK4/6 inhibitor combination therapies is a significant challenge 46,47. In this context, the combination of SHR6390 with endocrine therapy, including tamoxifen and fulvestrant, exerted synergistic antitumor activity in ER-positive breast cancer compared with each monotherapy.…”

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confidence: 99%

Preclinical characterization of SHR6390, a novel CDK 4/6 inhibitor, in vitro and in human tumor xenograft models

Long

et al. 2019

Cancer Science

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Inhibition of the cyclin‐dependent kinase (CDK) 4/6‐retinoblastoma (RB) pathway is an effective therapeutic strategy against cancer. Here, we performed a preclinical investigation of the antitumor activity of SHR6390, a novel CDK4/6 inhibitor. SHR6390 exhibited potent antiproliferative activity against a wide range of human RB‐positive tumor cells in vitro, and exclusively induced G 1 arrest as well as cellular senescence, with a concomitant reduction in the levels of Ser780‐phosphorylated RB protein. Compared with the well‐known CDK4/6 inhibitor palbociclib, orally administered SHR6390 led to equivalent or improved tumor efficacy against a panel of carcinoma xenografts, and produced marked tumor regression in some models, in association with sustained target inhibition in tumor tissues. Furthermore, SHR6390 overcame resistance to endocrine therapy and HER2‐targeting antibody in ER‐positive and HER2‐positive breast cancer, respectively. Moreover, SHR6390 combined with endocrine therapy exerted remarkable synergistic antitumor activity in ER‐positive breast cancer. Taken together, our findings indicate that SHR6390 is a novel CDK4/6 inhibitor with favorable pharmaceutical properties for use as an anticancer agent.

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confidence: 99%

Preclinical characterization of SHR6390, a novel CDK 4/6 inhibitor, in vitro and in human tumor xenograft models

Long

et al. 2019

Cancer Science

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“…The discrepancies observed between glucose uptake and glycolysis dependency may be due to the fact that the enhanced glucose uptake observed in the ER + /HER2 − PDR cells does not result in increasing glucose catabolism but rather fuels alternative (i.e., anabolic) pathways that diverge from glycolytic intermediates such as pentose phosphate, hexosamine and/or serine biosynthesis. Indeed, palbociclib treatment in MCF7 has been shown to enhance pentoses levels, a readout of the oxidative branch of the pentose phosphate pathway [35]. These anabolic pathways would provide building blocks necessary for proliferating cells and nicotinamide adenine dinucleotide phosphate (NADPH) essential to counteract the potential oxidative stress enhancement that occurs in cells under therapeutic pressure.…”

Section: Discussionmentioning

confidence: 99%

Glucose Metabolic Reprogramming of ER Breast Cancer in Acquired Resistance to the CDK4/6 Inhibitor Palbociclib+

Lorito

Bacci

Smiriglia

et al. 2020

Cells

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The majority of breast cancers express the estrogen receptor (ER) and are dependent on estrogen for their growth and survival. Endocrine therapy (ET) is the standard of care for these tumors. However, a superior outcome is achieved in a subset of ER positive (ER+)/human epidermal growth factor receptor 2 negative (HER2−) metastatic breast cancer patients when ET is administrated in combination with a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor, such as palbociclib. Moreover, CDK4/6 inhibitors are currently being tested in ER+/HER2+ breast cancer and reported encouraging results. Despite the clinical advances of a combinatorial therapy using ET plus CDK4/6 inhibitors, potential limitations (i.e., resistance) could emerge and the metabolic adaptations underlying such resistance warrant further elucidation. Here we investigate the glucose-dependent catabolism in a series of isogenic ER+ breast cancer cell lines sensitive to palbociclib and in their derivatives with acquired resistance to the drug. Importantly, ER+/HER2− and ER+/HER2+ cell lines show a different degree of glucose dependency. While ER+/HER2− breast cancer cells are characterized by enhanced aerobic glycolysis at the time of palbociclib sensitivity, ER+/HER2+ cells enhance their glycolytic catabolism at resistance. This metabolic phenotype was shown to have prognostic value and was targeted with multiple approaches offering a series of potential scenarios that could be of clinical relevance.

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“…Exposure of xenoestrogens was implicated in breast cancer risk (Pastor-Barriuso et al 2016) as well as resistance to breast cancer treatment (Goodson et al 2011;Warth et al 2018) due to their endocrine actions. The median urinary level of BP-3 was 0:137 lM, and PP was 0:161 lM in nonpregnant women in participating in the NHANES by the CDC (Calafat et al 2010;Woodruff et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Effects of Benzophenone-3 and Propylparaben on Estrogen Receptor–Dependent R-Loops and DNA Damage in Breast Epithelial Cells and Mice

Majhi

Sharma

Roberts

et al. 2020

Environ Health Perspect

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BACKGROUND: Endocrine-disrupting chemicals have been shown to have broad effects on development, but their mutagenic actions that can lead to cancer have been less clearly demonstrated. Physiological levels of estrogen have been shown to stimulate DNA damage in breast epithelial cells through mechanisms mediated by estrogen-receptor alpha (ERa). Benzophenone-3 (BP-3) and propylparaben (PP) are xenoestrogens found in the urine of >96% of U.S. population. OBJECTIVES: We investigated the effect of BP-3 and PP on estrogen receptor-dependent transactivation and DNA damage at concentrations relevant to exposures in humans. METHODS: In human breast epithelial cells, DNA damage following treatment with 17b-estradiol (E 2), BP-3, and PP was determined by immunostaining with antibodies against c-H2AX and 53BP1. Estrogenic responses were determined using luciferase reporter assays and gene expression. Formation of R-loops was determined with DNA: RNA hybrid-specific S9.6 antibody. Short-term exposure to the chemicals was also studied in ovariectomized mice. Immunostaining of mouse mammary epithelium was performed to quantify R-loops and DNA damage in vivo. RESULTS: Concentrations of 1 lM and 5 lM BP-3 or PP increased DNA damage similar to that of E 2 treatment in a ERa-dependent manner. However, BP-3 and PP had limited transactivation of target genes at 1 lM and 5 lM concentrations. BP-3 and PP exposure caused R-loop formation in a normal human breast epithelial cell line when ERa was introduced. R-loops and DNA damage were also detected in mammary epithelial cells of mice treated with BP-3 and PP. CONCLUSIONS: Acute exposure to xenoestrogens (PP and BP-3) in mice induce DNA damage mediated by formation of ERa-dependent R-loops at concentrations 10-fold lower than those required for transactivation. Exposure to these xenoestrogens may cause deleterious estrogenic responses, such as DNA damage, in susceptible individuals.

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Metabolomics Reveals that Dietary Xenoestrogens Alter Cellular Metabolism Induced by Palbociclib/Letrozole Combination Cancer Therapy

Cited by 56 publications

References 53 publications

Preclinical characterization of SHR6390, a novel CDK 4/6 inhibitor, in vitro and in human tumor xenograft models

Preclinical characterization of SHR6390, a novel CDK 4/6 inhibitor, in vitro and in human tumor xenograft models

Glucose Metabolic Reprogramming of ER Breast Cancer in Acquired Resistance to the CDK4/6 Inhibitor Palbociclib+

Effects of Benzophenone-3 and Propylparaben on Estrogen Receptor–Dependent R-Loops and DNA Damage in Breast Epithelial Cells and Mice

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