The impact of tumour pH on cancer progression: strategies for clinical intervention

Ward, Carol; Meehan, James; Gray, Mark; Murray, Alan F.; Argyle, David; Kunkler, Ian; Langdon, Simon P.

doi:10.37349/etat.2020.00005

Cited by 70 publications

(51 citation statements)

References 280 publications

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“…Apart from cancer-specific intracellular alkalization, the protumoral effects of the acidification of the TME are the second main metabolic and molecular issue in cancer growth and dissemination, either in BC and/or other human malignant tumors [ 111 ]. Its damaging effects are several: (a) locally stimulating tissue invasion and destruction, mainly by increasing the effects of invadopodia; (b) systematically disrupting the immune defense mechanisms of the organism and, in this way, fostering uncontrolled tumor progression; and (c) increasing MDR to most chemotherapeutic agents.…”

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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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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show abstract

“…Under hypoxia, glycolysis mainly occurs in tumor cells, and excess lactate is pumped out in the tumor microenvironment, which creates a proton gradient across the membrane of cancer cells. Because of the proton gradient, protons are taken up by nearby cancer cells, which further decreases the intracellular pH in these cells ( Corbet et al, 2016 ; Ward et al, 2020 ). Increased acidity activates the endoplasmic reticulum protein SREBP-1c, which translocates to the nucleus and enhances the expression of genes and enzymes involved in the fatty acid pathway.…”

Section: Discussionmentioning

confidence: 99%

Repurposing Combination Therapy of Voacamine With Vincristine for Downregulation of Hypoxia-Inducible Factor-1α/Fatty Acid Synthase Co-axis and Prolyl Hydroxylase-2 Activation in ER+ Mammary Neoplasia

Singh

Roy

Kumar

et al. 2021

Front. Cell Dev. Biol.

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Graphical AbstractMechanism of VOA and VIN to inhibit fatty acid synthesis in DMBA-induced mammary gland carcinoma of albino Wistar rats. Hypoxia-activated HIF-1α enhances lactate acidosis in the tumor microenvironment, and dysregulated pH in the tumor microenvironment activates SREBP-1c and FASN expression to speed up the fatty acid synthesis required for plasma membrane synthesis in rapidly proliferating cells. VOA- and VIN-activated PHD-2 enhanced the proteolytic degradation of HIF, thus inhibiting fatty acid synthesis. HIF-1α, hypoxia-inducible factor-1α; SREBP-1c, sterol regulatory element-binding protein-1c; FASN, fatty acid synthesis; PHD-2, prolyl hydroxylase-2.

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“…In the context of pH modification, the acidic microenvironment resulting from tumor-derived lactic acid was shown to prevent lactic acid export from cytotoxic T-cell lymphocytes (CTLs), impairing their metabolism and consequently immune function such as proliferation, cytokine production, and infiltration [ 101 ]. In turn, loss of T-cell function results in decreased immune clearance of tumor or aberrant cells [ 102 ]. Initially, it was thought that tumor cells’ ability to resist chemotherapeutic agents was only due to aberrant cellular responses within the tumor cell itself.…”

Section: Mechanism Of Chemoresistancementioning

confidence: 99%

Defining the Role of GLI/Hedgehog Signaling in Chemoresistance: Implications in Therapeutic Approaches

Chai

Sugumar

Al-Shanon

et al. 2021

Cancers

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Insight into cancer signaling pathways is vital in the development of new cancer treatments to improve treatment efficacy. A relatively new but essential developmental signaling pathway, namely Hedgehog (Hh), has recently emerged as a major mediator of cancer progression and chemoresistance. The evolutionary conserved Hh signaling pathway requires an in-depth understanding of the paradigm of Hh signaling transduction, which is fundamental to provide the necessary means for the design of novel tools for treating cancer related to aberrant Hh signaling. This review will focus substantially on the canonical Hh signaling and the treatment strategies employed in different studies, with special emphasis on the molecular mechanisms and combination treatment in regard to Hh inhibitors and chemotherapeutics. We discuss our views based on Hh signaling’s role in regulating DNA repair machinery, autophagy, tumor microenvironment, drug inactivation, transporters, epithelial-to-mesenchymal transition, and cancer stem cells to promote chemoresistance. The understanding of this Achilles’ Heel in cancer may improve the therapeutic outcome for cancer therapy.

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The impact of tumour pH on cancer progression: strategies for clinical intervention

Cited by 70 publications

References 280 publications

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

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

Repurposing Combination Therapy of Voacamine With Vincristine for Downregulation of Hypoxia-Inducible Factor-1α/Fatty Acid Synthase Co-axis and Prolyl Hydroxylase-2 Activation in ER+ Mammary Neoplasia

Defining the Role of GLI/Hedgehog Signaling in Chemoresistance: Implications in Therapeutic Approaches

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