Propranolol suppresses bladder cancer by manipulating intracellular pH via NHE1

Hu, Qian; Hu, Jiali; Chen, Cuiyu; Wang, Yan; Wan, Jielin; Ouyang, Jing; Yi, Hanying; Wang, Shiyu; Huang, Weihua; Liu, Jie; Zhang, Wei; McLeod, Howard L.; Xu, Ran; He, Yijing

doi:10.21037/tau-22-113

Cited by 6 publications

(3 citation statements)

References 30 publications

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“…NHE is a critical pH regulator responsible for maintaining normal pH conditions and removing excess H + from the cell for survival [30]. NHE1, which is crucial for intracellular pH regulation and upregulated in many cancer types [24,31,32], has been shown to contribute to tumor progression and drug resistance.…”

Section: Discussionmentioning

confidence: 99%

Metformin sensitizes hepatocellular carcinoma to sorafenib by facilitating NHE1 degradation

Tian

Yan

et al. 2023

Preprint

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Sorafenib is a first-line chemotherapy drug for advanced hepatocellular carcinoma (HCC), but the drug resistance appeared over time. Hypoxia and acidosis are common features of the microenvironment, which contribute to the drug resistance. Here, we verified that metformin could enhance the sensitivity of HCC cells to sorafenib under hypoxia. Furthermore, metformin altered the pH levels and reversed the acidification of extracellular environment. Mechanistically, metformin promoted the ubiquitination and degradation of NHE1, a sodium-hydrogen exchanger-1, which altered the pH regulation and decreased the sensitivity of HCC cells to chemotherapy. Finally, lung metastasis mice model, subcutaneous xenograft mice model, and orthotopic recurrence mice model were used to confirm the synergistic effects of metformin in vivo. In conclusion, metformin might be a promising adjuvant therapy to enhance the effectiveness of sorafenib in HCC patients.

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Section: Discussionmentioning

confidence: 99%

Metformin sensitizes hepatocellular carcinoma to sorafenib by facilitating NHE1 degradation

Tian

Yan

et al. 2023

Preprint

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“…Anti-tumor effects of beta blockers were demonstrated on bladder cancer cell lines treated with the beta-blocker propranolol. Propranolol exhibited anti-proliferative and pro-apoptotic effects in vitro and in vivo on mouse xenografts by modulating Na + /H + exchange as well acting on immune cells to activate a systemic immune response [125].…”

Section: Do Neurons Support Cancer Growth And/or Inhibit It?mentioning

confidence: 99%

The Bladder Tumor Microenvironment Components That Modulate the Tumor and Impact Therapy

Patwardhan,

Mahendran

2023

IJMS

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The tumor microenvironment (TME) is complex and involves many different cell types that seemingly work together in helping cancer cells evade immune monitoring and survive therapy. The advent of single-cell sequencing has greatly increased our knowledge of the cell types present in the tumor microenvironment and their role in the developing cancer. This, coupled with clinical data showing that cancer development and the response to therapy may be influenced by drugs that indirectly influence the tumor environment, highlights the need to better understand how the cells present in the TME work together. This review looks at the different cell types (cancer cells, cancer stem cells, endothelial cells, pericytes, adipose cells, cancer-associated fibroblasts, and neuronal cells) in the bladder tumor microenvironment. Their impact on immune activation and on shaping the microenvironment are discussed as well as the effects of hypertensive drugs and anesthetics on bladder cancer.

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“…Most recently, and still within the pH-centric therapeutic paradigm, an increasing number of promising repurposed drugs are being introduced in the pharmacological armamentarium available to clinicians (off-label use). Some of them, such as the betablocker propranolol, inhibit NHE1 inducing anti-proliferative and pro-apoptotic effects and also activate an anti-tumor immune response in vivo [72]. Furthermore, melatonin has been shown to act as an anticancer drug in glioblastoma via lowering of the pHi [73], in this way also inhibiting the Warburg effect [74].…”

Section: Therapeutic Implications: Closing Gapsmentioning

confidence: 99%

The Prime and Integral Cause of Cancer in the Post-Warburg Era

Harguindey¹,

Reshkin

Alfarouk³

2023

Cancers

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Back to beginnings. A century ago, Otto Warburg published that aerobic glycolysis and the respiratory impairment of cells were the prime cause of cancer, a phenomenon that since then has been known as “the Warburg effect”. In his early studies, Warburg looked at the effects of hydrogen ions (H+), on glycolysis in anaerobic conditions, as well as of bicarbonate and glucose. He found that gassing with CO2 led to the acidification of the solutions, resulting in decreased rates of glycolysis. It appears that Warburg first interpreted the role of pH on glycolysis as a secondary phenomenon, a side effect that was there just to compensate for the effect of bicarbonate. However, later on, while talking about glycolysis in a seminar at the Rockefeller Foundation, he said: “Special attention should be drawn to the remarkable influence of the bicarbonate…”. Departing from the very beginnings of this metabolic cancer research in the 1920s, our perspective advances an analytic as well as the synthetic approach to the new “pH-related paradigm of cancer”, while at the same time addressing the most fundamental and recent changing concepts in cancer metabolic etiology and its potential therapeutic implications.

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Propranolol suppresses bladder cancer by manipulating intracellular pH via NHE1

Cited by 6 publications

References 30 publications

Metformin sensitizes hepatocellular carcinoma to sorafenib by facilitating NHE1 degradation

Metformin sensitizes hepatocellular carcinoma to sorafenib by facilitating NHE1 degradation

The Bladder Tumor Microenvironment Components That Modulate the Tumor and Impact Therapy

The Prime and Integral Cause of Cancer in the Post-Warburg Era

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