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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