pH regulators and their inhibitors in tumor microenvironment

Liao, Senyi; Wu, Guang; Xie, Zhizhong; Lei, Xiaoyong; Yang, Xiaoyan; Huang, Sheng; Deng, Xiangping; Wang, Zhe; Tang, Guotao

doi:10.1016/j.ejmech.2024.116170

Cited by 10 publications

(1 citation statement)

References 220 publications

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“…Indirect evidence supporting the hypothesis that increasing CO 2 in the tumor microenvironment could be a valid medical approach was identified in scientific literature. Liao et al (2024) demonstrate that modifying the extracellular pH of the tumor microenvironment has an antitumor effect. They explain that the acidic tumor microenvironment is primarily caused by lactic acid production rather than CO 2 , due to abnormal mitochondrial activity in tumor cells.…”

Section: Discussionmentioning

confidence: 93%

Translational insights into the hormetic potential of carbon dioxide: from physiological mechanisms to innovative adjunct therapeutic potential for cancer

Gaspary,

Edgar,

Lopes

et al. 2024

Front. Physiol.

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BackgroundCarbon dioxide (CO2), traditionally viewed as a mere byproduct of cellular respiration, plays a multifaceted role in human physiology beyond simple elimination through respiration. CO2 may regulate the tumor microenvironment by significantly affecting the release of oxygen (O2) to tissues through the Bohr effect and by modulating blood pH and vasodilation. Previous studies suggest hypercapnia (elevated CO2 levels) might trigger optimized cellular mechanisms with potential therapeutic benefits. The role of CO2 in cellular stress conditions within tumor environments and its impact on O2 utilization offers a new investigative area in oncology.ObjectivesThis study aims to explore CO2’s role in the tumor environment, particularly how its physiological properties and adaptive responses can influence therapeutic strategies.MethodsBy applying a structured translational approach using the Work Breakdown Structure method, the study divided the analysis into six interconnected work packages to comprehensively analyze the interactions between carbon dioxide and the tumor microenvironment. Methods included systematic literature reviews, data analyses, data integration for identifying critical success factors and exploring extracellular environment modulation. The research used SMART criteria for assessing innovation and the applicability of results.ResultsThe research revealed that the human body’s adaptability to hypercapnic conditions could potentially inform innovative strategies for manipulating the tumor microenvironment. This could enhance O2 utilization efficiency and manage adaptive responses to cellular stress. The study proposed that carbon dioxide’s hormetic potential could induce beneficial responses in the tumor microenvironment, prompting clinical protocols for experimental validation. The research underscored the importance of pH regulation, emphasizing CO2 and carbonic acid’s role in modulating metabolic and signaling pathways related to cancer.ConclusionThe study underscores CO2 as vital to our physiology and suggests potential therapeutic uses within the tumor microenvironment. pH modulation and cellular oxygenation optimization via CO2 manipulation could offer innovative strategies to enhance existing cancer therapies. These findings encourage further exploration of CO2’s therapeutic potential. Future research should focus on experimental validation and exploration of clinical applications, emphasizing the need for interdisciplinary and collaborative approaches to tackle current challenges in cancer treatment.

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Section: Discussionmentioning

confidence: 93%

Translational insights into the hormetic potential of carbon dioxide: from physiological mechanisms to innovative adjunct therapeutic potential for cancer

Gaspary,

Edgar,

Lopes

et al. 2024

Front. Physiol.

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Bicyclic Sultams: From Organic Chemistry to Pharmaceutical Science

Chen,

Wang

2024

Asian J Org Chem

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Cyclic sulfonamides (sultams) widely distributed in pharmaceuticals due to their abundant biological activities. Currently, many pharmaceuticals with bicyclic sultam scaffold have been approved, some of them even have become first‐line medicines. In this concept, representative synthetic methodologies towards bicyclic sultams were selected and discussed. Construction of bicyclic γ‐ and δ‐sultams were the focus due to their pivotal role in medicinal chemistry. Most of the methodologies were focus on the construction of the sultam ring, including intramolecular N‐central cyclization (INC), oxidative cyclization (OC), carbanion‐mediated sulfonamide intramolecular cyclization (CSIC), transition‐metal catalyzed cyclization (TMCC) and ring closing metathesis (RCM). Name reactions such as Michael addition and Heck reaction were also applied to the construction of bicyclic sultams. In addition, this concept also discussed the enzyme‐catalytic reactions and some special reactions due to their unique properties.

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