The Interplay of Dysregulated pH and Electrolyte Imbalance in Cancer

Alfarouk, Khalid O.; Ahmed, Samrein B M; Ahmed, Ahmed; Elliott, Robert L.; Ibrahim, Muntaser E.; Ali, Heyam Saad; Wales, Christian C.; Nourwali, Ibrahim; Aljarbou, Ahmed N.; Bashir, Adil; Alhoufie, Sari T. S.; Alqahtani, Saad S.; Cardone, Rosa Angela; Fais, Stefano; Harguindey, Salvador; Reshkin, Stephan J.

doi:10.3390/cancers12040898

Cited by 42 publications

(34 citation statements)

References 217 publications

(255 reference statements)

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“…Activity of voltage-gated sodium channels on the cancer cell membrane helps regulate proliferation, migration, and invasion rather than excitability 14 . Similar to pH dysregulation in cancer, electrolyte imbalance also has a role in tumorigenesis 15 , 16 . Thus, being able to measure [Na + ] across different compartments in vivo could be considered as an important biomarker.…”

Section: Introductionmentioning

confidence: 99%

Imaging the transmembrane and transendothelial sodium gradients in gliomas

Khan

Walsh

Mihailovic

et al. 2021

Sci Rep

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Under normal conditions, high sodium (Na+) in extracellular (Na+e) and blood (Na+b) compartments and low Na+ in intracellular milieu (Na+i) produce strong transmembrane (ΔNa+mem) and weak transendothelial (ΔNa+end) gradients respectively, and these manifest the cell membrane potential (Vm) as well as blood–brain barrier (BBB) integrity. We developed a sodium (23Na) magnetic resonance spectroscopic imaging (MRSI) method using an intravenously-administered paramagnetic polyanionic agent to measure ΔNa+mem and ΔNa+end. In vitro 23Na-MRSI established that the 23Na signal is intensely shifted by the agent compared to other biological factors (e.g., pH and temperature). In vivo 23Na-MRSI showed Na+i remained unshifted and Na+b was more shifted than Na+e, and these together revealed weakened ΔNa+mem and enhanced ΔNa+end in rat gliomas (vs. normal tissue). Compared to normal tissue, RG2 and U87 tumors maintained weakened ΔNa+mem (i.e., depolarized Vm) implying an aggressive state for proliferation, whereas RG2 tumors displayed elevated ∆Na+end suggesting altered BBB integrity. We anticipate that 23Na-MRSI will allow biomedical explorations of perturbed Na+ homeostasis in vivo.

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Section: Introductionmentioning

confidence: 99%

Imaging the transmembrane and transendothelial sodium gradients in gliomas

Khan

Walsh

Mihailovic

et al. 2021

Sci Rep

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“…The pHi alkalinity results in the upregulation of the utilization of glucose (Glycolysis + Pentose Phosphate Pathway), while it slows down the Krebs cycle [ 7 , 28 ]. Therefore, NHE1 over-expression reprograms the metabolic cell machinery to undergo Warburg metabolism and produce lactate, which is translocated extracellularly, creating an interstitial acidity that stimulates the already diseased tumor milieu [ 40 ]. After that, the acid pHe recruits the pro-inflammatory immune cells with their cytokines, further supporting the invasiveness process, diminishing the efficacy of many chemotherapeutic agents, stimulating proteases and fostering the metastatic transformation cascade [ 41 , 42 ].…”

Section: Breast Cancer Ph-related Etiology and Pathogenesis The mentioning

confidence: 99%

Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New H+-Centered Anticancer Paradigm of the Late Post-Warburg Era

Harguindey¹,

Alfarouk

Orozco³

et al. 2020

IJMS

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A brand new approach to the understanding of breast cancer (BC) is urgently needed. In this contribution, the etiology, pathogenesis, and treatment of this disease is approached from the new pH-centric anticancer paradigm. Only this unitarian perspective, based upon the hydrogen ion (H+) dynamics of cancer, allows for the understanding and integration of the many dualisms, confusions, and paradoxes of the disease. The new H+-related, wide-ranging model can embrace, from a unique perspective, the many aspects of the disease and, at the same time, therapeutically interfere with most, if not all, of the hallmarks of cancer known to date. The pH-related armamentarium available for the treatment of BC reviewed here may be beneficial for all types and stages of the disease. In this vein, we have attempted a megasynthesis of traditional and new knowledge in the different areas of breast cancer research and treatment based upon the wide-ranging approach afforded by the hydrogen ion dynamics of cancer. The concerted utilization of the pH-related drugs that are available nowadays for the treatment of breast cancer is advanced.

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“…The extracellular environment of solid tumors is acidic, with a pH between 6.5 and 6.9, whereas normal tissues is alkaline, with a pH between 7.2 and 7.5 (3). Tissue acidosis can result in tumor progression (4). Therefore, interventions targeting the acidic microenvironment of tumors may provide new therapeutic opportunities.…”

Section: Introductionmentioning

confidence: 99%

TMEM206 is a potential prognostic marker of hepatocellular carcinoma

et al. 2020

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Transmembrane proteins are involved in the transportation of materials into and out of cells. The transmembrane protein (TMEM) family is a collection of poorly described transmembrane proteins that serve important roles in tumor development and progression. A number of TMEM proteins have been discovered. A newly discovered TMEM protein, TMEM206, transports ions across the membrane under physiological and pathological conditions, generating an acidic environment, which serves an important role in the microenvironment. However, the prognostic value and regulatory mechanisms of action of TMEM206 in tumors is unclear. The aim of the present study was to evaluate the prognostic value and regulation mechanisms of TMEM206 in tumors. Firstly, the expression of TMEM206 in tumors and normal tissues was assessed using the GEPIA and Oncomine databases and the results revealed that TMEM206 expression increased or decreased depending on the type of tumor. Subsequently, using the Human Protein Atlas and the Kaplan-Meier plotter, the findings of the present study revealed that TMEM206 is related to the prognosis of hepatocellular carcinoma. In order to explore the mechanism of TMEM206 in promoting tumor progression, GEO and cBioPortal were used to determine genes that may be co-expressed with TMEM206. MetaScape was used to identify the signaling pathways that TMEM206 may participate in. Finally, miRWalk, miRDB and TargetScan were used to identify miRNAs that may regulate the expression of TMEM206 and the findings revealed that 2 miRNA (hsa-miR-325 and hsa-miR-510-5p) were involved. In conclusion, upregulation of TMEM206 is associated with poor prognosis in patients with hepatocellular carcinoma.

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The Interplay of Dysregulated pH and Electrolyte Imbalance in Cancer

Cited by 42 publications

References 217 publications

Imaging the transmembrane and transendothelial sodium gradients in gliomas

Imaging the transmembrane and transendothelial sodium gradients in gliomas

Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New H+-Centered Anticancer Paradigm of the Late Post-Warburg Era

TMEM206 is a potential prognostic marker of hepatocellular carcinoma

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