Antitumor Effect of the Atypical Retinoid ST1926 in Acute Myeloid Leukemia and Nanoparticle Formulation Prolongs Lifespan and Reduces Tumor Burden of Xenograft Mice

Abstract

Acute myeloid leukemia (AML) is one of the most frequent types of blood malignancies. It is a complex disorder of undifferentiated hematopoietic progenitor cells. The majority of patients generally respond to intensive therapy. Nevertheless, relapse is the major cause of death in AML, warranting the need for novel treatment strategies. Retinoids have demonstrated potent differentiation and growth regulatory effects in normal, transformed, and hematopoietic progenitor cells. All- retinoic acid (ATRA) is the paradigm of treatment in acute promyelocytic leukemia, an AML subtype. The majority of AML subtypes are, however, resistant to ATRA. Multiple synthetic retinoids such as ST1926 recently emerged as potent anticancer agents to overcome such resistance. Despite its lack of toxicity, ST1926 clinical development was restricted due to its limited bioavailability and rapid excretion. Here, we investigate the preclinical efficacy of ST1926 and polymer-stabilized ST1926 nanoparticles (ST1926-NP) in AML models. We show that sub-μmol/L concentrations of ST1926 potently and selectively inhibited the growth of ATRA-resistant AML cell lines and primary blasts. ST1926 induced-growth arrest was due to early DNA damage and massive apoptosis in AML cells. To enhance the drug's bioavailability, ST1926-NP were developed using Flash NanoPrecipitation, and displayed comparable anti-growth activities to the naked drug in AML cells. In a murine AML xenograft model, ST1926 and ST1926-NP significantly prolonged survival and reduced tumor burden. Strikingly, ST1926-NP antitumor effects were achieved at four fold lower concentrations than the naked drug. These results highlight the promising use of ST1926 in AML therapy and encourage its further development..

The synthetic retinoid ST1926 attenuates prostate cancer growth and potentially targets prostate cancer stem‐like cells

“…Treatment with ST1926 for 24 hours induced an S phase increase by 39% and 18% in DU145 and PC3, respectively ( P = 0.16 for DU145; P = 0.295 for PC3), and by 64% and 34% at 48 hours in DU145 and PC3 cells, respectively ( P = 0.325 for DU145; P = 0.193 for PC3). These results are in agreement with previous reports demonstrating that ST1926 treatment induces the S phase arrest among different solid and hematological malignant cells …”

“…However, cancer cells can develop resistance to the natural retinoids, which prompted the development of new synthetic retinoids with a more specific and less toxic mechanism of actions than the natural ones . One of the promising synthetic retinoids with antineoplastic activities, increased bioavailability, and reduced toxicity is the adamantyl retinoid ST1926 …”

“…Based on the favorable antineoplastic properties of ST1926, we studied its antitumor properties and mechanism of action in PCa 2D and 3D in vitro, and in vivo models. Previous studies have shown that retinoids inhibit 5α‐reductase, an enzyme that is involved in steroid metabolism .…”

“…Although the exact mechanism of action of synthetic retinoids is not fully understood, their antiproliferative and proapoptotic effects are attributed to their ability to induce both receptor‐dependent and ‐independent mechanisms. Promising synthetic retinoids with antineoplastic activities include N‐(4‐hydroxyphenyl) retinamide (4HPR), 6‐[3‐(1‐adamantyl)‐4‐hydroxyphenyl]‐2‐naphthalene carboxylic acid (CD437), and ST1926; an analog of CD437 …”

“…Orally administered ST1926, has potent antitumor effects on both solid tumors and hematological malignancies . We investigated ST1926 mode of action in PCa in vitro and in vivo models and assessed its effect in targeting an enriched population of PCa stem‐like/progenitor cells.…”