Cotargeting Cyclin D1 Starts a New Chapter in Lung Cancer Prevention and Therapy

Kim, Edward S.; Lee, John; Wistuba, Ignacio I.

doi:10.1158/1940-6207.capr-11-0143

Cited by 14 publications

(10 citation statements)

References 21 publications

(22 reference statements)

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“…Cyclin D1 has also been shown to be a downstream target of several signal transduction pathways mediated by such oncogenes as Neu, Ras, and β-catenin. A recent study supports the promise of co-targeting Cyclin D1 as a predictive and personalizing approach for lung cancer prevention and therapy [34]. Furthermore, ACh acting through mAChR has been shown to lead to cell proliferation by activation of MAPK, ERK1/2 and regulation of cell cycle progression [11], [16].…”

Section: Discussionmentioning

confidence: 79%

A Novel Muscarinic Antagonist R2HBJJ Inhibits Non-Small Cell Lung Cancer Cell Growth and Arrests the Cell Cycle in G0/G1

Hua¹,

Wei²,

Liu³

et al. 2012

PLoS ONE

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Lung cancers express the cholinergic autocrine loop, which facilitates the progression of cancer cells. The antagonists of mAChRs have been demonstrated to depress the growth of small cell lung cancers (SCLCs). In this study we intended to investigate the growth inhibitory effect of R2HBJJ, a novel muscarinic antagonist, on non-small cell lung cancer (NSCLC) cells and the possible mechanisms. The competitive binding assay revealed that R2HBJJ had a high affinity to M3 and M1 AChRs. R2HBJJ presented a strong anticholinergic activity on carbachol-induced contraction of guinea-pig trachea. R2HBJJ markedly suppressed the growth of NSCLC cells, such as H1299, H460 and H157. In H1299 cells, both R2HBJJ and its leading compound R2-PHC displayed significant anti-proliferative activity as M3 receptor antagonist darifenacin. Exogenous replenish of ACh could attenuate R2HBJJ-induced growth inhibition. Silencing M3 receptor or ChAT by specific-siRNAs resulted in a growth inhibition of 55.5% and 37.9% on H1299 cells 96 h post transfection, respectively. Further studies revealed that treatment with R2HBJJ arrested the cell cycle in G0/G1 by down-regulation of cyclin D1-CDK4/6-Rb. Therefore, the current study reveals that NSCLC cells express an autocrine and paracrine cholinergic system which stimulates the growth of NSCLC cells. R2HBJJ, as a novel mAChRs antagonist, can block the local cholinergic loop by antagonizing predominantly M3 receptors and inhibit NSCLC cell growth, which suggest that M3 receptor antagonist might be a potential chemotherapeutic regimen for NSCLC.

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Section: Discussionmentioning

confidence: 79%

A Novel Muscarinic Antagonist R2HBJJ Inhibits Non-Small Cell Lung Cancer Cell Growth and Arrests the Cell Cycle in G0/G1

Hua¹,

Wei²,

Liu³

et al. 2012

PLoS ONE

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“…However, as multifunctional agents, retinoids are especially well-suited to combination therapies [159]. From a long line of studies it appears that to best exploit the potential of retinoid pharmacology optimal combinations with other agents will have to be identified and the issues of resistance and toxicity addressed systematically in preclinical models and relevant clinical trials.…”

Section: The Use Of Retinoids For Cancer Preventionmentioning

confidence: 99%

Retinoids and rexinoids in cancer prevention: from laboratory to clinic

Uray

Dmitrovsky

Brown

2016

Seminars in Oncology

131

102

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Early in the age of modern medicine the consequences of vitamin A deficiency drew attention to the fundamental link between retinoid-dependent homeostatic regulation and malignant hyperproliferative diseases. The term retinoid includes a handful of endogenous and a large group of synthetic derivatives of vitamin A. These multifunctional lipid-soluble compounds directly regulate target genes of specific biological functions and critical signaling pathways to orchestrate complex functions from vision to development, metabolism and inflammation. Many of the retinoid activities on the cellular level have been well characterized and translated to the regulation of processes like differentiation and cell death, which play critical roles in the outcome of malignant transformation of tissues. In fact, retinoid-based differentiation therapy of acute promyelocytic leukemia was one of the first successful examples of molecularly targeted treatment strategies. The selectivity, high receptor binding affinity and the ability of retinoids to directly modulate gene expression programs present a distinct pharmacological opportunity for cancer treatment and prevention. However, to fully exploit their potential, the adverse effects of retinoids must be averted. In this review we provide an overview of the biology of retinoid (activated by nuclear retinoic acid receptors, RARs) and rexinoid (engaged by nuclear retinoid X receptors, RXRs) action concluded from a long line of preclinical studies, in relation to normal and transformed states of cells. We will also discuss the past and current uses of retinoids in the treatment of malignancies, the potential of rexinoids in the cancer prevention setting, both as single agents and in combinations.

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“…[The ongoing phase III adjuvant trial of erlotinib in EGFR mutant patients (RADIANT) should help clarify this issue.] In advanced lung cancer, overexpression of cyclin D1 is predictive of response to a combination of erlotinib and bexarotene (98, 103); patients whose resected tumors overexpressed cyclin D1 could be treated with this combination. Other potential tumor characteristics/patient treatment assignments could be as follows: KRAS and BRAF mutations/Ras/Raf inhibitor, EML4-ALK translocation/ALK inhibitor, VEGFR overexpression/vandetanib or other VEGFR inhibitors, and PI3K pathway alterations (65, 104)/PI3K/Akt inhibitor (21).…”

Section: Personalized Prevention: the Battle Is Onmentioning

confidence: 99%

The BATTLE to Personalize Lung Cancer Prevention through Reverse Migration

Gold

Kim

Lee

et al. 2011

Cancer Prevention Research

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Agents can enter clinical development for cancer prevention either initially or after previous development for a different indication, such as arthritis, with both approaches consuming many years of development before an agent is fully evaluated for cancer prevention. We propose the following, third approach: Reverse migration, that is, importing agents, targets and study designs to personalize interventions, and concepts developed in advanced cancer to the setting of cancer prevention. Importing these “ready-made” features from therapy will allow reverse migration to streamline preventive-agent development. We recently reported the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial of personalized lung-cancer therapy and now propose the reverse-migration development of personalized lung-cancer prevention based on the BATTLE model.

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Cotargeting Cyclin D1 Starts a New Chapter in Lung Cancer Prevention and Therapy

Cited by 14 publications

References 21 publications

A Novel Muscarinic Antagonist R2HBJJ Inhibits Non-Small Cell Lung Cancer Cell Growth and Arrests the Cell Cycle in G0/G1

A Novel Muscarinic Antagonist R2HBJJ Inhibits Non-Small Cell Lung Cancer Cell Growth and Arrests the Cell Cycle in G0/G1

Retinoids and rexinoids in cancer prevention: from laboratory to clinic

The BATTLE to Personalize Lung Cancer Prevention through Reverse Migration

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