title: Prodifferentiation Activity of Novel Vitamin D₂ Analogs PRI-1916 and PRI-1917 and Their Combinations with a Plant Polyphenol in Acute Myeloid Leukemia Cells.
abstract: 1α,25-dihydroxyvitamin D₃ (1,25D3) is a powerful differentiation inducer for acute myeloid leukemia (AML) cells. However, 1,25D3 doses required for differentiation of AML cells may cause lethal hypercalcemia in vivo. There is evidence that vitamin D₂ is less toxic than vitamin D₃ in animals. Here, we determined the differentiation effects of novel analogs of 1α,25-dihydroxyvitamin D₂ (1,25D2), PRI-1916 and PRI-1917, in which the extended side chains of their previously reported precursors (PRI-1906 and PRI-1907, respectively) underwent further 24Z (24-cis) modification. Using four human AML cell lines representing different stages of myeloid maturation (KG-1a, HL60, U937, and MOLM-13), we found that the potency of PRI-1916 was slightly higher or equal to that of PRI-1906 while PRI-1917 was significantly less potent than PRI-1907. We also demonstrated that 1,25D2 was a less effective differentiation agent than 1,25D3 in these cell lines. Irrespective of their differentiation potency, all the vitamin D₂ derivatives tested were less potent than 1,25D3 in transactivating the DR3-type vitamin D response elements. However, similar to 1,25D3, both 1,25D2 and its analogs could strongly cooperate with the plant polyphenol carnosic acid in inducing cell differentiation and inhibition of G1-S cell cycle transition. These results indicate that the 24Z modification has contrasting effects on the differentiation ability of PRI-1906 and PRI-1907 and that the addition of a plant polyphenol could result in a similar extent of cell differentiation induced by different vitamin D compounds. The enhanced antileukemic effects of the tested combinations may constitute the basis for the development of novel approaches for differentiation therapy of AML.
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Ben Gurion University of the Negev, Beer Sheva 841051, Israel. matanna@post.bgu.ac.il.
authors.forename: Matan
authors.initials: M
authors.lastname: Nachliely
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Ben Gurion University of the Negev, Beer Sheva 841051, Israel. ehudshar@gmail.com.
authors.forename: Ehud
authors.initials: E
authors.lastname: Sharony
authors.affiliation: Department of Chemistry and Department of Pharmacology, Pharmaceutical Research Institute, Warsaw 01-793, Poland. n.bolla@ifarm.eu.
authors.forename: Narasimha Rao
authors.initials: NR
authors.lastname: Bolla
authors.affiliation: Department of Chemistry and Department of Pharmacology, Pharmaceutical Research Institute, Warsaw 01-793, Poland. a.kutner@ifarm.eu.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Kutner
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Ben Gurion University of the Negev, Beer Sheva 841051, Israel. misha@bgu.ac.il.
authors.forename: Michael
authors.initials: M
authors.lastname: Danilenko
mesh_terms: D045784:Abietanes / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D004872:Ergocalciferols / Q000737:chemistry / Q000494:pharmacology*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D059808:Polyphenols / Q000494:pharmacology*
chemical_list: C533599:24a-homo-1,15-dihydroxyergocalciferol; D045784:Abietanes; D004872:Ergocalciferols; C000616594:PRI-1916; C000616595:PRI-1917; D010936:Plant Extracts; D059808:Polyphenols; C018381:salvin
keywords: acute myeloid leukemia; analogs of 1α,25-dihydroxyvitamin D2; carnosic acid; cell cycle distribution; cell differentiation; retinoid X receptor; vitamin D receptor