International Research Journal of Oncology

Destabilization of Abnormal Methylation Enzymes as the Only Viable Option for the Elimination of Cancer Stem Cells to Save Cancer Patients

Ming C. Liau *

CDA Therapeutics, Inc., 3308 Sky Run Court, Missouri City, TX 77459, USA.

Christine L. Craig

CDA Therapeutics, Inc., 3308 Sky Run Court, Missouri City, TX 77459, USA.

Linda L. Baker

CDA Therapeutics, Inc., 3308 Sky Run Court, Missouri City, TX 77459, USA.

*Author to whom correspondence should be addressed.

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Abstract

Cytotoxic chemotherapy was a tragic by-product of World War II. It was the major therapeutic modality employed but failed to win the War on Cancer during 1971-1976 declared by President Nixon. Despite the failure, killing of cancer cells (CCs) remained the commanding principle of cancer establishments to guide development of cancer therapies throughout. Apparently, this commanding principle is incorrect, since cancer mortality continues to increase.

Wound unhealing leads to the evolution of cancer. Progenitor stem cells (PSCs) must proliferate and undergo terminal differentiation in order to complete wound healing. PSCs are cells that possess aberrant methylation enzymes (MEs), which provide them a significant growth advantage. In order to safeguard cells with aberrant MEs and maintain control over them, nature produces chemo-surveillance, which is composed of wound healing metabolites, differentiation inducers (DIs), and differentiation helper inducers (DHIs). The breakdown of chemo-surveillance, which prevents PSCs from undergoing terminal differentiation, is the cause of wound unhealing. The nature does not have a mechanism to detect the breakdown of chemo-surveillance to make the correction. PSCs are forced to proliferate, which is limited by contact inhibition, another protection mechanism the nature created to limit the buildup of normal stem cells. PSCs are then forced to evolve into cancer stem cells to escape contact inhibition. It takes a single hit to silence TET-1 enzyme, an enzyme responsible to direct lineage transitions, to turn PSCs into cancer stem cells (CSCs). The evolution of CSCs from PSCs is quite easy, since PSCs are equipped with very active abnormal MEs. The propagation of CSCs still cannot heal the wound, because the problem is the collapse of chemo-surveillance. The CSCs will be forced to progress to faster growing CCs by chromosomal abnormalities such as translocations to activate oncogenes, or deletions to inactivate suppressor genes. So, the correct solution of cancer is to restore chemo-surveillance by providing DIs and DHIs to destabilize abnormal MEs to achieve terminal differentiation of PSCs and CSCs which are closely linked to wound unhealing. Killing of CSCs and PSCs cannot heal the wound. Therefore, destabilization of abnormal MEs to achieve terminal differentiation of CSCs is the only viable option to take out CSCs by healing the wound to save cancer patients. The elimination of CSCs is essential to the success of cancer therapy. We have carried out extensive studies of natural and unnatural DIs and DHIs for the manufacturing of CDA formulations to save cancer patients.

Keywords: Cancer therapies, cancer cells, cancer stem cells, differentiation inducers, differentiation helper inducers, methylation enzymes, progenitor stem cells

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References

Liau MC, Fruehauf JP. It has been half a century since President Nixon declared war on cancer: Destabilization of abnormal methylation enzymes has the blessing of the nature to win the war on cancer. Adv Complement Alt Med. 2020;6(1):538-539.

Liau MC, Craig CL. Wound healing metabolites to heal cancer and unhealed wounds. Intl Res J Oncol. 2022;6(3):8-20.

Google search on cancer statistics-NCI.

Liau MC. A perfect cancer drug must be able to take out both cancer cells and cancer stem cells, and to restore the functionality of chemo-surveillance. 3rd International Conference on Medicinal Chemistry and Drug Design. 2021;13.

Virchow R. Die cellular pathologie in ihrer begrundung auf physiologische und pathologische gewebelehve. Hirschwald. 1858;16:440.

Dvorak HF. Tumors: Wounds that do not heal. N Engl J Med. 1986;315(26):1650-1659.

MacCarthy-Morrough L, Martin IP. The hallmark of cancer are also the hallmarks of wound healing. Science Signaling. 2020; 13:648.

Liau MC, Baker LL. Wound healing, evolution of cancer and war on cancer. Intl Res J Oncol. 2021;4(3):13-20.

Liau MC, Craig CL. On the mechanism of wound healing and the impact of wound on cancer evolution and cancer therapy. Intl Res J Oncol. 2021;5(3):25-31.

Liau MC, Craig CL. No scar as an indication of perfect wound healing, ugly scar as imperfect wound healing and cancer as failed wound healing. J Cancer Tumor Intl. 2022;12(1):29-34.

Liau MC, Craig CL. Wound unhealing as a grave issue of cancer. Intl Res J Oncol. 2023;6(1):97-103.

Liau MC, Szopa M, Burzynski B, Burzynski SR. Chemo-surveillance: A novel concept of the natural defense mechanism against cancer. Drug Exptl Clin Res. 1989; 13(Suppl.1):72-82.

Liau MC, Craig CL. Chemo-surveillance as a natural mechanism to ensure perfection of wound healing to avoid cancer evolution and to cure cancer. In: New Horizones in Medicine and Medical Research. 2022;6: 21-28.

Kudo Y, Tateishi K, Yamamoto K, Yamamoto S, Asaoka Y, Ijichi H, et al. Loss of 5-hydroxymethylcytosine is accompanied with malignant cellular transformation. Cancer Sci. 2012;103(4): 670-676.

Ficz GM, Gibben JG. Loss of 5-hydroxymethylcytosine in cancer: Cause or consequence? Genomics. 2014;104(5): 352-357.

Liau MC,Baker LL. Destruction promotes the proliferation of progenitor stem cells and cancer stem cells. Therefore, non-destruction strategy is a better choice of cancer therapy. J Pharmacol Pharmaceu Pharmacovig. 2020;4:029. DOI: 10.24966/PPP-5459/100029.

Monger-Sacca M, Dimrino S, De Maria R. Biological and clinical implication of cancer stem cells in primary brain tumors. Front Oncol. 2013;3:6.

Liu YC, Lee IC, Chen PY. Biominetic brain tumor niche regulates glioblastoma cells toward a cancer stem cell phenotype. J Newrooncol. 2018;137(3):511-522.

Zhou S, Schuetz JD, Bunting KD, Colapietro AM, et al. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med. 2001;7(9):1028-1034.

Zhang M, Atkinson RL, Rosen JM. Selective targeting of radiation resistant tumor initiating cells. Proc Natl Acad Sci USA. 2010;107(8):3522-3527.

Moitra K, Lou H, Dean M. Multidrug efflug pumps and cancer stem cells: Insight into therapy resistance and therapeutic development. Clin Pharmacol Ther. 2011; 89(4):491-502.

Frame FM, Maitland NU. Cancer stem cells, model of study and implication of therapy resistance mechanisms. Adv Exp Med Biol. 2011;720(2):105-118.

Liau MC, Craig CL, Baker LL. Elimination of cancer stem cells is essential to save cancer patients. Intl J Res Oncol. 2024; 3(1):1-9.

Liau MC, Craig CL,Baker LL. Modifications of imperfect cancer drugs to become perfect cancer drugs to save cancer patients. Br J Healthcare Med Res. 2024; 11(2):1-17.

Liau MC, Craig DL, Baker LL. CDA formulations as persuasive good cancer drugs to save cancer patients. Intl J Clin Oncol Cancer Res. 2024;9(1):15-24.

Liau MC, Baker LL. Cancer patients’s lives matter. Adv Complement Alt Med. 2023; 6(5):638-640.

Liau MC, Craig CL, Baker LL. A drastic change of cancer leaderships to save cancer patients. In: New Advance in Medicine and Medical Science. 2023;7:61-69.

Liau MC, Craig CL, Baker LL. Royal family’s cancer diagnoses offer a supreme authority to rectify cancer therapies to save cancer patients. London J Med Health Res. 2024;24(5):31-43.

Liau MC, Lin GW, Hurlbert RB. Partial purification and characterization of tumor and liver S-adenosylmethionine synthetases. Cancer Rs. 1977;37(2):427-435.

Liau MC, Chang CF, Giovanella BC. Demonstration of an altered S-adenosylmethionine synthetase in human malignant tumors xenografted into athymic nude mice. J Natl Cancer Inst. 1980;64(5): 1071-1075.

Liau MC, Zhuang P, Chiou GCY. Identification of the tumor factor of abnormal methylation enzymes as the catalytic subunit of telomerase. Clin Oncol Cancer Res. 2010;7(2):86-96.

Liau MC, Baker LL. The functionality of chemo-surveillance dictates the success of wound healing as well as cancer therapy. Novel Res Sci. 2021;7(2):1-3.

Liau MC, Craig CL. Baker LL. Exceptional allosteric regulation of methylation enzymes. In: Saraydin SU (ed), Novel Research Aspect in Medicine and Medical Research. 2023;4:38-56.

Liau MC, Craig CL, Baker LL. Restoration of chemo-surveillance as a top priority to save cancer patients. Intl Res J Oncol. 2023;6:227-237.

Liau MC, Lee SS, Burzynski SR. Hypomethylation of nucleic acids: A key to the induction of terminal differentiation. Intl J Exptl Clin Chemother. 1989;2:187-199.

Liau MC, Kim JH, Fruehauf JP. Destabilzation of abnormal methylation enzymes to combat cancer: The nature’s choice to win the war on cancer. Lambert Academic Publishing. 2020;978-620-2-66889-7.

Liau MC, Chang CF, Becker FF. Alteration of S-adenosylmethionine synthetases during chemical hepatocarcinoewnesis and in resulting carcinomas. Cancer Res. 1979; 39:2113-2119.

Kamparath BN, Liau MC, Burzynski B, Burzynski SR. Protective effect of Antineoplaston A10 in hepatocarcinogenesis induced by aflatoxin B1. Intl J Tiss React. 1990;12(Suppl.):43-50.

Liau MC, Craig CL, Baker LL. Wound healing process as the most appropriate modality of cancer therapy. Eur J Applied Sci. 2023;11(1):463-471.

Liau MC, Craig CL, Baker LL. Wound healing process as the best strategy to save cancer patients. London J Med Health Res. 2023;23(13):1-11.

Liau MC, Fruehauf JP. Cancer moonshot : Moonshot as a magic code to guide successful solution of tough challenges such as cancer. Intl J Res Oncol. 2023; 2(1):1-5.

Williamson PJ, Krugger AR, Reynolds PJ, Hamlin TJ, Oscier DG. Establishing the incidence of myelodysplastic syndromes. Br J Haematol. 1994;87(4):743-745.

Boula A, Vougarelis M, Giannouli S, Katrinakis G, Psyllaki M, Pontikoglou C, et al. Effect of CA2 of antitumor necrosis facter-alphs antibody theapy on hematopoiesis of patients with myelodysplastic syndromes. Clin Cancer Res. 2006;12(10):3099-3108.

Itkin T, Rafii S. Luekemia cells ”gas up’ leaky bone marrow blood vessels. Cancer Cell. 2017;32(3):276-278.

Passaro D, Di Tullio A, Abarrategi A, Rousault-Pierre K, Foster K, Ariza-McNaughton L, et al. Increased vascular permeabilityu in the bone marrow microenvironment contribute to disease progression and drug response in acute myeloid leukemia. Cancer Cell. 2017; 32(3):324-341.

Counter CM, Gupta J, Harley CB, Lever B. Telomerase activity in normal leukocytes and hematological malignancies. Blood. 1995;89(9):2315-2320.

Fu C, Chen Z. Telomerase activities in myelodysplastic syndromes. Chin Med J (Engl). 2002;115(10):1475-1478.

Woll PS, Kjallquist U, Chowdhury O, Doolittle H, Wedge DC, Thougjuea S, et al. Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo. Cancer Cell. 2014; 25(6):794-808.

Ma J. Differentiation therapy of malignant tumor and leukemia. CSCO Treaties on the Education of Clinical Oncology. 2007; 480-486.

Santi DV, Norment A, Garret CE. Covalent bond formation between a DNA-cytosine methyl-transferase of DNA containing 5-azacytosine. Proc Natl Acad Sci USA. 1984;81(22):6993-6997.

Liau MC. Pharmaceutical composition inducing cancer cell differentiation and the use for treatment and prevention of cancer thereof. US Patent. 2007;7232578 B2.

Prassana P, Shack S, Wilson VL, Samid D. Phenylacetate in chemoprevention of 5-aza-2’-deoxycytidine-induced carcinogenesis. Clin Cancer Res. 1995; 1(18):865-871.

Gaudet F, Hodgson JG, Eden A, Jackson-Grudby L, Gausman J, Gray JW, et al. Induction of tumor in mice by genomic hypomethylation. Science. 2003; 300(3618):489-492.

Palii SS, van Emburgh BO, Sankpal UT, Brown KD, Robertson KD. DNA methylation inhibitor 5-aza-2’-deoxycytidine induces reversible DNA damage that is distinctly influenced by DNA-methyltransferase 1 and 3B. Mol Cell Biol. 2008;28920:752-771.

Kezietepe T, Hedeshima T, Catley L, Raje N, Yasui H, Shiraishi N, et al. 5-Azacytidine, a methyltransferase inhibitor, induces ATR-mediated DNA-double strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicine and bortezomib against mytiple myeloma cells. Mol Cancer Ther. 2007;6(6):1718-1727.

Yang Q, Wu F, Wang F, Cai K, Zhang Y, Sun Q, et al. Impact of DNA methyltransferase inhibitor 5-azacytidine on cardiac development of zebrafish In vivo and cardiomyocyte proliferation, apoptosis, and the homeostasis of gene expression in vitro. J Cell Biochem. 2019;120(10):17549-17471.

Liau MC. Differentiation therapy of cancer. Bull Chin Cancer. 2002;11:104-107.

Liau MC. Abnormal methylation enzymes: A selective molecular target for differentiation therapy of cancer. Chin Pharm J. 2004;56:57-67.

Liau MC, Chang CF, Saunders GF, Tsai YH. S-Adenosylhomocysteine hydrolases as the primary target enzymes in androgen regulation of methylation complexes. Arch Biochem Biophys. 1981;208(1):261-272.

Prudova A, Bauman Z, Braun A, Vitvitsky V, Lu SC, Banerjee R. S-Adenosylmethionine stabilizes cystathionine beta-syntase and modulate redox capacity. Proc Natl Acad Sci USA. 2006;103(17):6489-6494.

Chiba P, Wallner C, Kaizer E. S-Adenosylmethionine metabolism in HL-60 cells: Effect of cell cycle and differentiation. Biochim Biophys Acta. 1988;971(1):38-45.

Liau MC, Baker LL. Abnormal methylation enzymes as the bullseye of targeted cancer therapies. Nov Res Sci. 2021;7(4):1-3.

Liau MC, Lee SS, Burzynski SR. Differentiation inducing components of Antineoplaston A5. Adv Exptl Clin Chemother. 1988;6/88:9-26.

Liau MC, Burzynski SR. Separation of active anticancer components of Antineoplaston A2, A3 and A5. Intl J Tiss React. 1990;12(Suppl.):1-18.

Liau MC, Ashraf A, Lee SS, Henry LB, Burzynski SR. Riboflavin as a minor active anticancer component of Antineoplaston A2 and A5. Intl J Tiss React. 1990; 12(Suppl.):19-26.

Liau MC, Liau CP, Burzynski SR. Potentiation of retinoid acid-indued terminal differentiation by phenylacetic acid and related chemicals. Intl J Exptl Clin Chemother. 1992;5:9-17.

Liau MC, Huang LJ, Lee JH, Chen SC, Kuo SC. Development of differentiation helper inducers for the differentiation therapy of cancer. Chin Pharm J. 1998;50: 289-303.

Liau MC, Liau CP. Methyltransferase inhibitors as excellent differentiation helper inducers for differentiation therapy of cancer. Bull Chin Cancer. 2002;11:166-168.

Liau MC, Fruehauf PA, Zheng ZH, Fruehauf JP. Development of synthetic cell differentiation agent formulaitons for the prevention and therapy of cancer via targeting of cancer stem cells. Cancer Stu Ther J. 2019;4:1-15.

Liau MC, Kim JH, Fruehauf JP. Potentiation of ATRA activity in HL-60 cells by targeting methylation enzymes. J Pharmacol Pharmaceu Pharmacovigi. 2019;3:009.

DOI: 10.24966/PPP-5649/100009.

Liau MC, Kim JH, Fruehauf JP. In pursuance of differentiation inducers to combat cancer via targeting of abnormal methylation enzymes. J Cancer Tumor Intl. 2020;10(2):39-47.

Liau MC, Kim JH, Fruehauf JP. Arachidonic acid and its metabolites as the surveillance differentiation inducers to protect healthy people from becoming cancer patients. Clin Pharmacol Toxicol Res. 2021;4(1):7-10.

Huang M, Ye Y, Chen S, Chai JR, Wang ZY. Use of all trans-retinoic acid in the treatment promyelocytic leukemia. Blood. 1988;72:567-572.

Bourgead MF, Beasoncon F. Induction of 2’, 5’-oligoadenylate synthetase by retinoic acid in two transformed human cell lines. Cancer Res. 1084;44:5355-5360.

Mordey JE. Hormone, aging and endocrines in the elderly. In: Felig P, Frohman LA: Emdocrinology and Metabolism. 4th ed. McGrow Hill Inc, Medical Publishing Division. New York. 2001;1455-1482.

Le Coutre P, Mologni L, Cleris L, Marchesi E, Buchdunger E. Giardini R, et al. In vivo eradication of human BCR/ABL- positive leukemia cells with an ABL kinase inhibitor. J Natl Cancer Inst. 1999;91:163-168.

Oliveira LB de, Chao BMP, Bini ACD, Cordeiro MER, Carraro E. PI3K/AKT/mTOR Inhibitor Drug Candidates for the Treatment of Hormone Resistant Breast Cancer: A Systematic Review. J. Adv. Med. Med. Res. [Internet]. 2024 Apr. 6 [cited 2024 May 21];36(5):120-7. Available:https://www.journaljammr.com/index.php/JAMMR/article/view/5421

Sentoso JW, Putra A, Alif I. Targeting Unique Features of Quiescent Cancer Stem Cells to Overcome Resistance and Recurrence in Cancer Therapy: A Review. J. Can. Tumor Int. [Internet]. 2024 Apr. 5 [cited 2024 May 21];14(1):18-31. Available:https://journaljcti.com/index.php/JCTI/article/view/247

Batlle E, Clevers H. Cancer stem cells revisited. Nature medicine. 2017 Oct 1; 23(10):1124-34.