Arachidonic Acid and Its Metabolites as Differentiation Inducers for the Perfection of Wound Healing to Avoid Cancer and to Beat Cancer | Chapter 12 | Current Aspects in Pharmaceutical Research and Development Vol. 1

 The goal of this research is to look at the role of arachidonic acid and its metabolites in wound healing, cancer progression, and cancer treatment. The Chinese FDA authorised Cell Differentiation Agent-2 (CDA-2) as a promising hypomethylation agent for the treatment of Myelo Dysplastic Syndrome (MDS). MDS is a condition caused only by cancer stem cells (CSCs). A medication that is effective in the treatment of MDS may also be effective in the treatment of CSCs. Differentiation Inducers (DIs) and Differentiation Helper Inducers (DHIs) are the active components of CDA-2 (DHIs). DIs are compounds that can remove telomerase from aberrant Methylation Enzymes (MEs) present in human malignancies and primitive stem cells such Progenitor Stem Cells (PSCs) and Embryonic Stem Cells (ESCs) (ESCs). CDA-2's main DIs were organic acids that did not absorb UV light. It proved challenging to purify CDA-2 DIs for identification without using UV absorbance as a guide. As a result, we looked for persons who could serve as DIs. Prosta Glandin E2 (PGE2) piqued our interest since it was associated to wound healing, which is a major biological function of PSCs and CSCs. Eradication of CSCs has been a major focus of our research. PGE2 was proven to be beneficial as a DI in a prior study, which prompted us to explore at other PGs that could work as DIs with improved activity and stability, as well as less negative side effects. The two PGs that worked well as DIs in the development of CDA formulations were PGJ2 and 16, 16-dimethylPGE2. PGJ2 was active at doses ranging from 4 to 17 M, with a high of 86 percent NBT+cells induction at 4 M. 17. M. 16, 16-dimethylPGE2 was active at doses ranging from 10 to 32 M, with a high of 83 percent NBT+cells being induced at 27 M. BicycloPGE2 and Arachidonic Acid (AA) had similar DI actions. Between 20 and 42 M, both were moderately active, with a maximum of 42 percent -52 percent NBT+cells at 42 M. Although AA is not very effective as a DI, pregnenolone's significant synergistic potentiation of DI action can increase its effectiveness as a DI. CDA-2 DIs were found in liposomal complexes with pregnenolone or in connection with cell membranes in prior research. bits of membrane CDA-2 could very possibly have AA as a major DI. As a result, AA could be an effective surveillance DI for cancer prevention in healthy people. This study also found that metabolites involved in wound healing play a role in chemo-surveillance.

Author (S) Details

Ming C. Liau
Department of Medicine, University of California, Irvine Medical Center, CA, USA.

Dr. Jai-Hyun Kim,
Department of Medicine, University of California, Irvine Medical Center, CA, USA.

John P. Fruehauf
Department of Medicine, University of California, Irvine Medical Center, CA, USA.



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An Approach in Pursuance of Differentiation Inducers to Combat Cancer via Targeting of Abnormal Methylation Enzymes | Chapter 8 | Highlights on Medicine and Medical Research Vol. 2

A preparation of urinary differentiation inducers (DIs) and differentiation helper inducers (DHIs) was a cell differentiation agent-2 (CDA-2) that was a promising hypomethylating agent approved by the Chinese FDA for the treatment of myelodysplastic syndrome (MDS). DIs are chemicals that are capable of extracting telomerase from frequently occurring abnormal MEs in human cancers. An organic acid without UV absorption is the main DI of CDA- 2. Without UV absorption as a reference, the DI of CDA-2 for identification was hard to purify. Thus, in this research, we sought possible candidates to act as DIs.

Cancer MEs are abnormal due to telomerase interaction. We were, of course, searching for telomerase inhibitors as potential candidates for DIs. Our attention was drawn to Prostaglandin E2 (PGE2) because it was involved in wound healing, a major biological mission of progenitor stem cells (PSCs) and cancer stem cells (CSCs). A big focus of our studies has been eradicating CSCs. In addition, PGE2 suits the definition of CDA-2's major DI.

Induction of terminal differentiation (TD) by NBT assay of HL-60 cells was used to assess the behavior of chemicals as DIs. The creation of cells was based on cell numbers. Two well-known DIs are all-trans retinoic acid (ATRA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). With a maximum induction of 89 percent NBT+ cells at 3 μM, ATRA showed a wide active dosage range from 0.2 to 4.5 μM. With a maximum induction of 84 percent NBT+ cells at 0.4 nM, TPA showed a narrow active dosage range of 0.2 to 0.6 nM. The two telomerase inhibitors analysed were BIBR1532 and bodine. As DIs, both were found involved. BIBR1532 was active in the 30 to 75 μM dosage range, with a maximum of 86 percent induction at 63 μM. In the 60 to 98 μM dosage range, Bodine was active with a maximum induction of 80 percent at 98 μM. PGE2 was active in the 20 to 70 μM dosage range, with a maximum of 80 percent induction at 56 μM. 16, 16-dimethyl PGE2 has the potential to exhibit effective inhibitory activity against spontaneous cancer development as an acceptable DI. DIs may behave as effective DHIs to other DIs at dosages not active as DIs. BIBR1532, boldine, and PGE2 RIsub0.5 as DHIs were respectively 2.02 μM, 3.11 μM, and 0.92 μM. DIs alone can not induce NBT+ cells to reach 100 percent, no matter how successful. The peak value reached by ATRA was 95 percent (89 percent plus 6 percent blank). When ATRA was used alone in the treatment of acute promyelocytic leukemia, incomplete TD induction was the explanation for recurrent recurrence (APL). To avoid recurrence, a combination of ATRA and a DHI could induce NBT+ cells to reach 100 per cent.

Author (s) Details

Ming C. Liau
CDA Therapeutics, Tustin, California, USA.

Jai-Hyun Kim
Chao Family Comprehensive Cancer Center, University of California, Irvine Medical Center, Orange, California, USA.

John P. Fruehauf
Chao Family Comprehensive Cancer Center, University of California, Irvine Medical Center, Orange, California, USA.

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