ST1926, an orally active synthetic retinoid, induces apoptosis in chronic myeloid leukemia cells and prolongs survival in a murine model

Nasr, Rihab; Hmadi, Raed; El-Eit, R.; Iskandarani, Ahmad; Jabbour, Mark N.; Zaatari, Ghazi; Mahon, François‐Xavier; Pisano, Claudio; Darwiche, Nadine

doi:10.1002/ijc.29407

Cited by 18 publications

(30 citation statements)

References 47 publications

(131 reference statements)

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“…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 …”

Section: Resultssupporting

confidence: 94%

“…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 …”

Section: Discussionmentioning

confidence: 99%

“…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 …”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Bahmad

Samman

Monzer

et al. 2019

Molecular Carcinogenesis

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Retinoids are vitamin A derivatives that regulate crucial biological processes such as cellular proliferation, apoptosis, and differentiation. The use of natural retinoids in cancer therapy is limited due to their toxicity and the acquired resistance by cancer cells. Therefore, synthetic retinoids were developed, such as the atypical adamantyl retinoid ST1926 that provides enhanced bioavailability and reduced toxicity. We have assessed the in vitro and in vivo antitumor properties and mechanism of action of ST1926 in targeting cancer stem‐like cells population of human prostate cancer (PCa) cell lines, DU145 and PC3, and mouse PCa cell lines, PLum‐AD and PLum‐AI. We demonstrated that ST1926 substantially reduced proliferation of PCa cells and induced cell cycle arrest, p53‐independent apoptosis, and early DNA damage. It also decreased migration and invasion of PCa cells and significantly reduced prostate spheres formation ability in vitro denoting sufficient eradication of the self‐renewal ability of the highly androgen‐resistant cancer stem cells. Importantly, ST1926 potently inhibited PCa tumor growth and progression in vivo. Our results highlight the potential of ST1926 in PCa therapy and warrant its clinical development.

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Section: Resultssupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Bahmad

Samman

Monzer

et al. 2019

Molecular Carcinogenesis

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“…The atypical retinoid E23-(40-hydroxyl-30-adamantylbiphenyl-4-yl) acrylic acid (ST1926, adarotene) counteracts growth of several tumor cells [1, 2], including rhabdomyosarcoma [3], neuroblastoma [4, 5], ovarian cancer [6-9], teratocarcinoma [10], chronic myeloid leukemia [11], acute myeloid leukaemia [12, 13], and adult T-cell leukemia/lymphoma [14]. ST1926 is at least in part effective by inducing apoptosis [1, 9, 13, 15].…”

Section: Introductionmentioning

confidence: 99%

Stimulation of Erythrocyte Cell Membrane Scrambling by Adarotene

Mischitelli¹,

Jemaàa²,

Fezai³

et al. 2017

Cell Physiol Biochem

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Background/Aims: The atypical retinoid E23-(40-hydroxyl-30-adamantylbiphenyl-4-yl) acrylic acid (ST1926, adarotene) is used in the treatment of malignancy. The effect of ST1926 is at least in part due to stimulation of apoptosis. Similar to apoptosis of nucleated cells, erythrocytes may enter eryptosis, the suicidal death of erythrocytes. Hallmarks of eryptosis include cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling involved in the stimulation of eryptosis includes increase of cytosolic Ca²⁺ activity [Ca²⁺]_i, oxidative stress and ceramide. The present study explored, whether adarotene induces eryptosis and, if so, to test for the involvement of Ca²⁺ entry, oxidative stress and ceramide. Methods: Flow cytometry was employed to estimate phosphatidylserine exposure at the cell surface from annexin-V-binding, cell volume from forward scatter, [Ca²⁺]_i from Fluo3-fluorescence, reactive oxygen species (ROS) formation from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. Results: A 48 hours exposure of human erythrocytes to adarotene (9 µM) significantly increased the percentage of annexin-V-binding cells, an effect paralleled by significant decrease of forward scatter, as well as significant increase of Fluo3-fluorescence, DCFDA fluorescence, and ceramide abundance. The effect of adarotene (9 µM) on annexin-V-binding was significantly blunted but not abolished by removal of extracellular Ca²⁺. Conclusions: Adarotene stimulates phospholipid scrambling of the erythrocyte cell membrane, an effect paralleled by and at least in part due to Ca²⁺ entry, oxidative stress and ceramide.

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The synthetic retinoid ST1926 as a novel therapeutic agent in rhabdomyosarcoma

Basma

Ghayad

Rammal

et al. 2015

Intl Journal of Cancer

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Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in children. Despite multiple attempts at intensifying chemotherapeutic approaches to treatment, only moderate improvements in survival have been made for patients with advanced disease. Retinoic acid is a differentiation agent that has shown some antitumor efficacy in RMS cells in vitro; however, the effects are of low magnitude. E23-(4 0 -hydroxyl-3 0 -adamantylbiphenyl-4-yl) acrylic acid (ST1926) is a novel orally available synthetic atypical retinoid, shown to have more potent activity than retinoic acid in several types of cancer cells. We used in vitro and in vivo models of RMS to explore the efficacy of ST1926 as a possible therapeutic agent in this sarcoma. We found that ST1926 reduced RMS cell viability in all tested alveolar (ARMS) and embryonal (ERMS) RMS cell lines, at readily achievable micromolar concentrations in mice. ST1926 induced an early DNA damage response (DDR), which led to increase in apoptosis, in addition to S-phase cell cycle arrest and a reduction in protein levels of the cell cycle kinase CDK1. Effects were irrespective of TP53 mutational status. Interestingly, in ARMS cells, ST1926 treatment decreased PAX3-FOXO1 fusion oncoprotein levels, and this suppression occurred at a post-transcriptional level. In vivo, ST1926 was effective in inhibiting growth of ARMS and ERMS xenografts, and induced a prominent DDR. We conclude that ST1926 has preclinical efficacy against RMS, and should be further developed in this disease in clinical trials.Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma, and the third most common solid tumor in children. 1 It accounts for 6% of all childhood cancers and approximately 40% of soft tissue sarcomas. 2,3 RMS likely arises from primitive mesenchymal progenitors that have undergone a limited program of myogenic differentiation, because of the expression of skeletal myogenic proteins in RMS tumors. 1,4 Rhabdomyosarcoma occurs in two major histological subtypes: embryonal (ERMS) and alveolar (ARMS) histologies. 1,4 ARMS is associated with a chromosomal translocation between the PAX3 or PAX7 and FOXO1 genes in approximately 55 and 22% of cases, respectively. 5 Patients presenting with ARMS tumors usually have a worse prognosis as compared to ERMS. The PAX-FOXO1 fusion transcript has been shown to exhibit a more potent transcriptional activation function than the PAX proteins alone, 6 and contributes to the invasive phenotype of ARMS, 7,8 making it an interesting target for therapeutic intervention. 9 Despite multiple attempts at intensifying chemotherapeutic approaches to treatment, limited improvements in survival have been made for patients with advanced-stage disease or recurrent RMS over the past 10 years. [10][11][12] This underlies the need for novel therapeutic approaches. 10,13 Retinoic acid is a morphogen and a major regulator of cellular proliferation, apoptosis and differentiation, 14 and has been investigated as differentiation therapy in multiple types of cancer, contributi...

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ST1926, an orally active synthetic retinoid, induces apoptosis in chronic myeloid leukemia cells and prolongs survival in a murine model

Cited by 18 publications

References 47 publications

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

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

Stimulation of Erythrocyte Cell Membrane Scrambling by Adarotene

The synthetic retinoid ST1926 as a novel therapeutic agent in rhabdomyosarcoma

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