Development of Good Cancer Drugs Effective against Cancer Stem Cells

Abstract

A right approach is essential to solve any illness. Cancer mortality remains at historic high and is still on the way to increase. The objective of this study is to find a right approach of cancer therapy to bring cancer mortality down. Myelodysplastic syndromes are diseases attributable entirely to cancer stem cells that can be used to screen good cancer drugs to bring down cancer mortality. Cancer is caused due to wound unhealing. Wound triggers biological and immunological responses. Biological response leads to the production of prostaglandins (PGs) which are good for wound healing. Immunological response prompts the production of tumor necrosis factor (TNF) which is bad for wound healing. TNF causes apoptosis of stem cells, thus triggering the proliferation of progenitor stem cells (PSCs) to repair wound damages. TNF is also named cachectin after its effect to cause cachexia symptom. A manifestation of cachexia symptom is the excessive urinary excretion of low molecular weight metabolites, resulting in the collapse of chemo-surveillance which is the nature’s creation of allosteric regulation to keep a check on abnormal methylation enzymes (MEs). PSCs are cells with abnormal MEs. On wound healing, efficient terminal differentiation of PSCs is a critical mechanism to heal wound. If wound is not healed properly, PSCs may be forced to evolve into cancer stem cells (CSCs) through a single hit to silence TET-1 enzyme, and then to progress to faster growing cancer cells (CCs) through chromosomal abnormalities such as translocations or deletions to activate oncogenes or to inactivate suppressor genes.  Myelodysplastic syndromes (MDS) are a classic case of cancer development at the stage of PSCs evolving to become CSCs. Therapy of MDS requires the differentiation of pathological CSCs to become functional erythrocytes, platelets or neutrophils. So far, Vidaza, Decitabine and cell differentiation agent-2 (CDA-2) are the three drugs approved for the therapy of MDS. Vidaza and Decitabine inactivate abnormal MEs through covalent bone formation between DNA methyltransferase and 5-azacytosine base incorporated into DNA, whereas CDA-2 destabilizes abnormal MEs through elimination of telomerase. Obviously, inactivation of abnormal MEs is the only way to achieve therapy of MDS. Elimination of CSCs is very critical to the success of cancer therapy. Thus, MDS can be used to screen good cancer drugs to fulfill the wish of President Biden to reduce cancer mortality.