The Prime and Integral Cause of Cancer in the Post-Warburg Era
Abstract
:Simple Summary
Abstract
1. Introduction: Otto Warburg Today: The pH Factor as the Missing Link
2. Why Warburg Was Right and Wrong at the Same Time
3. From the Initial pH-Glycolysis Associations to the Present State of the Art in Metabolic Cancer Research
4. On the Changing Hallmarks of Malignancy in pH-Related Metabolic Cancer Research
5. Therapeutic Implications: Closing Gaps
6. Conclusions: Towards Biological Unifications
Author Contributions
Funding
Acknowledgments
Dedication
Conflicts of Interest
References
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1920s. Discovery of the aerobic and fermentative glycolysis of tumors by Otto Warburg seminal and extraordinary discoveries. |
1956. Heated discussions, mainly between Otto Warburg and Sidney Weinhouse, with Arthur Schade and Dean Burk as witnesses, on the meaning of tumor cells glycolysis and respiration in cancer etiology. |
1960s and 1970s. Discovery of the stimulatory effects on glycolysis and carcinogenesis of different pH-elevating growth factors. |
1980s. Discovery of the Na+/H+ antiporter (NHE) and its inhibition in arresting cancer cell growth. |
1980s and 1990s. Increasing description of different membrane-bound hydrogen ion (H+) transporters (PTs) as well as a high pHi in cell transformation of fibroblasts. |
1990s. First demonstration that certain proton transport (PTs) stimulators induce cell transformation by increasing pHi while inhibiting H+ efflux inhibits cancer growth and facilitates the induction of cancer cell apoptosis. |
2000s. (A) Increasing research on the potential importance of proton transport inhibitors (PTI) in cancer treatment and the discovery of the carcinogenic effects of different Na+/H+ antiporter upregulating factors in cancer etiology, etiopathogenesis, growth and the metastatic process (virus, PTs, chemical carcinogens, etc.) (See Table 2). (B) Description of pH-unrelated hallmarks and new pH-related hallmarks of cancer. (C) First publications of pH-related integral measures as a concerted therapeutic approach to different human malignancies. |
2010s. Description of cancer proton reversal (CPR) as a highly selective cancer hallmark of cancer. An increasing recognition of the new pH-centric anticancer paradigm in basic and clinical oncology. Finally, the first explanations of the opposite relations between cancer and human neurodegenerative diseases (HNDDs). |
2020s. Extension of the Warburg effect to the pathogenesis of different human pathologies beyond cancer, including human neurodegenerative diseases and infections. |
Gene products such as Bcl-2 |
Virus (e.g., Human Papilloma Virus) |
Oncogenes and viral products (e.g., HPV-E7) |
Modification/mutations/over-expression in other pH transporters (PTs) and proton pumps (PPs) |
Chemical carcinogens (groundwater arsenic salts, polycyclic aromatic hydrocarbons) |
Chronic and intermittent hypoxia |
Mutations and genomic instability (BRCA1/2) |
Aging (which Warburg called “Time Caused Cancer”) |
Glucose overload |
Mitogens (VEGF isoforms, EGF, interleukin isoforms, TGF isoforms, PDGF isoforms, etc.) |
Hormones and cytokines (growth hormone, prolactin, glucocorticoids, etc.) |
p53 deficiency/mutations |
Immune evasion |
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Harguindey, S.; Reshkin, S.J.; Alfarouk, K.O. The Prime and Integral Cause of Cancer in the Post-Warburg Era. Cancers 2023, 15, 540. https://doi.org/10.3390/cancers15020540
Harguindey S, Reshkin SJ, Alfarouk KO. The Prime and Integral Cause of Cancer in the Post-Warburg Era. Cancers. 2023; 15(2):540. https://doi.org/10.3390/cancers15020540
Chicago/Turabian StyleHarguindey, Salvador, Stephan J. Reshkin, and Khalid O. Alfarouk. 2023. "The Prime and Integral Cause of Cancer in the Post-Warburg Era" Cancers 15, no. 2: 540. https://doi.org/10.3390/cancers15020540
APA StyleHarguindey, S., Reshkin, S. J., & Alfarouk, K. O. (2023). The Prime and Integral Cause of Cancer in the Post-Warburg Era. Cancers, 15(2), 540. https://doi.org/10.3390/cancers15020540