Lung and bladder cancers are mostly incurable because of the early development of drug resistance and metastatic dissemination. Hence, improved therapies that tackle these two processes are urgently needed to improve clinical outcome. We have identified RSK4 as a promoter of drug resistance and metastasis in lung and bladder cancer cells. Silencing this kinase, through either RNA interference or CRISPR, sensitized tumor cells to chemotherapy and hindered metastasis in vitro and in vivo in a tail vein injection model. Drug screening revealed several floxacin antibiotics as potent RSK4 activation inhibitors, and trovafloxacin reproduced all effects of RSK4 silencing in vitro and in/ex vivo using lung cancer xenograft and genetically engineered mouse models and bladder tumor explants. Through x-ray structure determination and Markov transient and Deuterium exchange analyses, we identified the allosteric binding site and revealed how this compound blocks RSK4 kinase activation through binding to an allosteric site and mimicking a kinase autoinhibitory mechanism involving the RSK4's hydrophobic motif. Last, we show that patients undergoing chemotherapy and adhering to prophylactic levofloxacin in the large placebo-controlled randomized phase 3 SIGNIFICANT trial had significantly increased ( = 0.048) long-term overall survival times. Hence, we suggest that RSK4 inhibition may represent an effective therapeutic strategy for treating lung and bladder cancer.
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http://dx.doi.org/10.1126/scitranslmed.aba4627 | DOI Listing |
Phytother Res
December 2024
Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, Craiova, Romania.
Recent research has increasingly focused on phytochemicals as promising anticancer agents, with glucosinolates (GSLs) and their hydrolytic derivatives playing a central role. These sulfur-containing compounds, found in plants of the Brassicales order, are converted by myrosinase enzymes into biologically active products, primarily isothiocyanates (ITCs) and indoles, which exhibit significant anticancer properties. Indole-3-carbinol, diindolylmethane, sulforaphane (SFN), phenethyl isothiocyanate (PEITC), benzyl isothiocyanate, and allyl isothiocyanate have shown potent anticancer effects in animal models, particularly in breast, prostate, lung, melanoma, bladder, hepatoma, and gastrointestinal cancers.
View Article and Find Full Text PDFCancer Causes Control
December 2024
Division of Public Health Sciences, Fred Hutchinson Cancer Center, 1100 Fairview Ave N, M4-C308, Seattle, WA, 98019, USA.
Purpose: The association between statin use and cancer survival has been investigated in previous studies with conflicting findings. This study aimed to assess the association between statin use following cancer diagnosis and survival in six common cancers using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database.
Methods: Individuals aged ≥ 66 years diagnosed with prostate cancer, colorectal cancer, lung cancer, bladder cancer, pancreatic cancer, or non-Hodgkin lymphoma (NHL) from 2008 through 2017 were identified.
Background: Previous observational studies examining the relationship between cadmium exposure and various cancers have yielded conflicting results. This study aims to comprehensively clarify the relationship between blood cadmium concentration (BCC) and nine specific cancers.
Methods: A retrospective analysis of National Health and Nutrition Examination Survey (NHANES) 1999-2018 identified 36,991 participants.
PLoS One
December 2024
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, United States of America.
Associations between vitamin D biochemical status and cancer may be modified by vitamin D binding protein isoforms which are encoded by GC (group-specific component). We examined interactions between serum 25-hydroxyvitamin D [25(OH)D], the Gc isoforms Gc1-1, Gc1-2, and Gc2-2, and cancer risk within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort based on 3,795 cases and 3,856 controls. Multivariable-adjusted logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) of cancer risk according to 25(OH)D quantiles, stratified by Gc isoform.
View Article and Find Full Text PDFZhongguo Zhong Yao Za Zhi
November 2024
Center for Evidence-based Chinese Medicine, Institute of Basic Research in Clinical Medicine,China Academy of Chinese Medical Sciences Beijing 100700, China.
Life is a dynamic and systematic whole, with organs interacting with each other. Traditional Chinese medicine(TCM) discusses the interaction between human tissue and organs through the Zangfu relations, while modern biological medicine clarifies physiological and pathological relationships through "organ crosstalk". From the perspective of "organ crosstalk", this article discussed the five classical Zangfu relations(lungs and large intestine, heart and small intestine, spleen and stomach, liver and gallbladder, and kidney and bladder) in TCM and their extension.
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