Superior effect of 9‐cis retinoic acid (RA) compared with all‐trans RA and 13‐cis RA on the inhibition of clonogenic cellgrowth and the induction of apoptosis in OCI/AML‐2 subclones: is the p53 pathway involved?

Abstract

Summary. In the present study, the effects of 9‐cis retinoic acid (RA) and 13‐cis RA on acute myeloblastic leukaemia (AML) cell growth and the induction of apoptosis as well as its relationship with bcl‐2 and p53 were compared with those of all‐trans RA (ATRA). The study was performed with the subclones of the retinoid‐sensitive OCI/AML‐2 cell line. The most prominent inhibitory effect on clonogenic cell growth and morphological apoptosis was shown by 9‐cis RA. In addition, Western blotting revealed the most obvious translocation of p53 from cytosol to nucleus in the case of 9‐cis RA, which was the only retinoid able to change the conformation of p53 from mutational to wild type, as demonstrated by flow cytometry. There was no difference between the retinoids in the downregulation of bcl‐2 as analysed by Western blotting and flow cytometry. The RA receptor (RAR)‐α antagonist had no effect on apoptosis in any of the three retinoids studied using the annexin V method. In conclusion, this study shows that 9‐cis RA was a more potent agent than ATRA or 13‐cis RA in inducing growth arrest and apoptosis in the OCI/AML‐2 subclones. The effect was associated with the downregulation of bcl‐2 and was hardly mediated through the RAR‐α receptor, but might be related to the activation of p53.

Differential regulation of CC chemokine receptors by 9-cis retinoic acid in the human mast cell line, HMC-1

“…Retinoids expressed in the liver and kidney has two stereoisomers known as 9CRA and ATRA (Pemrick et al, 1994). Depending on their isomers, retinoids have a variety of effects on leukemia therapy as well as the immune response (Huang et al, 1988;Sakashita et al, 1993;Koistinen et al, 2002). As shown in prior work on the comparative effects of retinoids in THP-1 cells (Kim et al, 2004), this study demonstrated that 9-CRA is more effective than ATRA for CCR2 down-regulation, and decreased cell migration induced by MCP-1 (Fig.…”

“…Retinoids, depending on their isoforms, have different effects on immunological response and cancer therapy (Huang et al, 1988;Sakashita et al, 1993;Koistinen et al, 2002). We examined whether CCR2 down-regulation in HMC-1 cells is differently regulated by two different retinoids, 9CRA and ATRA.…”

Sensitivity to DNA Damage Is a Common Component of Hormone-Based Strategies for Protection of the Mammary Gland

“…The same treatments were done as in A. A study done with the subclones of the retinoid-sensitive acute myeloblastic leukemia (OCI/AML-2) cell lines showed 9-cis RA had the most prominent effect of inducing apoptosis and inhibiting cell growth compared with all-trans and 13-cis RAs and that 9-cis RA was most effective at causing the translocation of p53 from cytosol to nucleus (27). Because the p53 pathway is involved in the protective response imparted by hormones (14), and retinoids in cell lines have been shown to induce p53 stability and transcriptional activity (38), we further investigated the relationship between p53 and retinoids in a whole-organ culture system.…”

“…Activation of p53 is another pathway by which retinoids may exert their effects. Numerous examples have been cited which indicate that retinoid exposure leads to the induction of p53 stability and transcriptional activities (25)(26)(27)(28).…”

Epigenome-Based Drug Repositioning in Acute Myeloid Leukemia

“…alitretinoin, panobinostat, and progesterone. Both alitretinoin, a geometric isomer of tretinoin currently used in the treatment of Acute Promyelocytic Leukemia (a subclass of AML) [34] , and panobinostat, a histone deacetylase inhibitor commonly used in multiple myeloma [35] , have been investigated for use in AML [36][37][38][39] . Lastly, while progesterone itself has not, to our knowledge, been suggested for AML treatment, a synthetic progestin, medroxyprogesterone acetate, has recently been suggested as a possible drug repositioning candidate for AML [40] .…”