Preclinical efficacy of the synthetic retinoid ST1926 for treating adult T-cell leukemia/lymphoma

Hajj, Hiba El; Khalil, Bariaa; Ghandour, Botheina; Nasr, Rihab; Shahine, Sharif Walid; Ghantous, Akram; Abdel-Samad, Rana; Sinjab, Ansam; Hasegawa, Hideki; Jabbour, Mark N.; Hall, William W.; Zaatari, Ghazi; Dbaibo, Ghassan; Pisano, Claudio; Bazarbachi, Ali; Darwiche, Nadine

doi:10.1182/blood-2014-03-560060

Cited by 34 publications

(63 citation statements)

References 51 publications

(65 reference statements)

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“…ST1926 was previously shown to be a potent DNA damaging agent in different hematological malignancies and solid tumors . The mechanism of genotoxic stress induced by ST1926 is still unclear.…”

Section: Discussionmentioning

confidence: 99%

“…ST1926, also known as Adarotene, is a novel adamantyl retinoid. It is a 6‐[3‐(1‐adamantyl)‐4‐hydroxyphenyl]‐2‐naphthalene carboxylic acid (CD437) analog that is very active against several hematological and solid malignancies and in in vivo cancer models . Due to its remarkable antineoplastic activities, ST1926 has entered phase I clinical trials in ovarian cancer .…”

mentioning

confidence: 99%

“…Importantly, orally administered ST1926 has been shown to induce a significant growth inhibition in human melanoma, ovarian carcinoma and neuroblastoma growing in nude mice, and to be effective in acute promyelocytic leukemia (APL), acute myeloid leukemia (AML) and adult T cell leukemia/lymphoma (ATL) SCID mouse models …”

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confidence: 99%

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

et al. 2015

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The tyrosine kinase inhibitor, imatinib, is the first line of treatment for chronic myeloid leukemia (CML) patients. Unfortunately, patients develop resistance and relapse due to bcr-abl point mutations and the persistence of leukemia initiating cells (LIC). Retinoids regulate vital biological processes such as cellular proliferation, apoptosis, and differentiation, in particular of hematopoietic progenitor cells. The clinical usage of natural retinoids is hindered by acquired resistance and undesirable side effects. However, bioavailable and less toxic synthetic retinoids, such as the atypical adamantyl retinoid ST1926, have been developed and tested in cancer clinical trials. We investigated the preclinical efficacy of the synthetic retinoid ST1926 using human CML cell lines and the murine bone marrow transduction/transplantation CML model. In vitro, ST1926 induced irreversible growth inhibition, cell cycle arrest and apoptosis through the dissipation of the mitochondrial membrane potential and caspase activation. Furthermore, ST1926 induced DNA damage and downregulated BCR-ABL. Most importantly, oral treatment with ST1926 significantly prolonged the longevity of primary CML mice, and reduced tumor burden. However, ST1926 did not eradicate LIC, evident by the ability of splenocytes isolated from treated primary mice to develop CML in untreated secondary recipients. These results support a potential therapeutic use of ST1926 in CML targeted therapy.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

et al. 2015

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“…Studies of arsenic and interferon treatment show potential clinical benefit, which may be due to inhibition of leukaemia cell initiating activity [15]. This effect may be enhanced by a synthetic retinoid, ST1926 [16 • ]. Recent data suggest an improved response with the addition to combination chemotherapy of an antibody to CCR4, a chemokine receptor overexpressed on ATL cells responsible for targeting leukocytes to the central nervous system and endothelial cells involved in angiogenesis [17 • ].…”

Section: Introductionmentioning

confidence: 99%

How does HTLV-1 cause adult T-cell leukaemia/lymphoma (ATL)?

Bangham

Ratner

2015

Current Opinion in Virology

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A typical person infected with the retrovirus human T-lymphotropic virus type 1 (HTLV-1) carries tens of thousands of clones of HTLV-1-infected T lymphocytes, each clone distinguished by a unique integration site of the provirus in the host genome. However, only 5% of infected people develop the malignant disease adult T cell leukaemia/lymphoma, usually more than 50 years after becoming infected. We review the host and viral factors that cause this aggressive disease.

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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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Preclinical efficacy of the synthetic retinoid ST1926 for treating adult T-cell leukemia/lymphoma

Abstract: Key Points The synthetic retinoid ST1926 induces apoptosis of ATL cells and prolongs survival of ATL mice. At the molecular level, ST1926 causes early DNA damage, upregulates p53, and downregulates Tax expression.

Cited by 34 publications

References 51 publications

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

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

How does HTLV-1 cause adult T-cell leukaemia/lymphoma (ATL)?

Stimulation of Erythrocyte Cell Membrane Scrambling by Adarotene

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