A Novel Atypical Retinoid Endowed with Proapoptotic and Antitumor Activity

Cincinelli, Raffaella; Dallavalle, Sabrina; Merlini, Lucio; Penco, Sergio; Pisano, Claudio; Carminati, Paolo; Giannini, Giuseppe; Vesci, Loredana; Gaetano, Carlo; Illy, Barbara; Zuco, Valentina; Supino, Rosanna; Zunino, Franco

doi:10.1021/jm025593y

Cited by 59 publications

(80 citation statements)

References 6 publications

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“…26 Such conclusion is also consistent with our recent finding that a novel related agent ST1926 is a potent inducer of apoptosis in spite of an almost complete loss of ability to transactivate RARs. 9 A novel observation of our previous study was the evidence that ST1926 is able to cause DNA strand breaks after a short-term exposure (6 h). The precise mechanism of this type of DNA lesion remains unknown.…”

Section: Discussionmentioning

confidence: 91%

“…7,8 Recently, we have reported that a related compound, ST1926 (Figure 1), characterized by an almost complete loss of ability to activate retinoid receptors, exhibited a high antiproliferative potency and marked ability to induce apoptosis. 9 In addition, ST1926 was found to induce DNA damage under conditions causing apoptotic effects. In an attempt to better elucidate the molecular and cellular basis of the apoptosis induced by ST1926, we have performed a study in an ovarian carcinoma cell system, including the parental IGROV-1 cells carrying wild-type p53 and a subline, IGROV-1/Pt1, selected for resistance to cisplatin and characterized by p53 mutation.…”

Section: Introductionmentioning

confidence: 99%

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Induction of apoptosis and stress response in ovarian carcinoma cell lines treated with ST1926, an atypical retinoid

et al. 2003

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To understand the molecular mechanisms mediating apoptosis induction by a novel atypical retinoid, ST1926, the cellular response to drug treatment was investigated in IGROV-1 ovarian carcinoma cells carrying wild-type p53 and a cisplatin-resistant p53 mutant subline (IGROV-1/Pt1). Despite a similar extent of drug-induced DNA strand breaks, the level of apoptosis was substantially higher in p53 wild-type cells. p53 activation and early upregulation of p53-target genes were consistent with p53-dependent apoptosis in IGROV-1 cells. Stress-activated protein kinases were activated in both cell lines in response to ST1926. This event and activation of AP-1 were more pronounced in IGROV-1/Pt1 cells, in which the modulation of DNA repair-associated genes suggests an increased ability to repair DNA damage. Inhibition of JNK or p38 stimulated ST1926-induced apoptosis only in IGROV-1 cells, whereas inhibition of ERKs enhanced apoptosis in both the cell lines. Such a pattern of cellular response and modulation of genes implicated in DNA damage response supports that the genotoxic stress is a critical event mediating drug-induced apoptosis. The results are consistent with apoptosis induction through p53-dependent andindependent pathways, regulated by MAP kinases, which likely play a protective role.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Induction of apoptosis and stress response in ovarian carcinoma cell lines treated with ST1926, an atypical retinoid

et al. 2003

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“…However, ST1926 was designed to have a styrene moiety replacing the naphthalene ring of CD437, resulting in a pharmacokinetically stable, highly orally bioavailable, and pharmacologically attainable in the plasma of patients at micromolar concentrations. 23,24 ST1926 is a potent inducer of DNA damage and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, we observed early induction of g-H2AX implicating ST1926 in eliciting DNA damage in treated malignant T cells as previously reported in other cancer models. 23,26,33,34,47 Although CD437 is also an inducer of DNA damage, ST1926 was shown to be more potent in a wide range of DNA lesions, including strand breaks, incomplete excision repair, and alkali-labile sites. 26 In vivo, ST1926 significantly prolonged survival in ATL mice ( Figure 4A-B) and clearly reduced micro-metastases within the liver parenchyma, as well as in the kidneys and lungs ( Figure 4E; data not shown).…”

Section: Discussionmentioning

confidence: 99%

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

Hajj¹,

Khalil²,

Ghandour

et al. 2014

Blood

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Retinoids

Dawson¹

2010

Burger's Medicinal Chemistry and Drug Discovery

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Retinoid drugs find major applications in the topical treatment of cutaneous proliferative disorders such as acne, psoriasis, and photoaging and cutaneous cancers such as cutaneous T‐cell lymphoma (CTCL) and Kaposi's sarcoma. Oral retinoids are successfully used to treat nodular/cystic acne, systemic CTCL, and acute promyelocytic leukemia. This overview of available retinoid drugs and those in the preclinical or clinical pipeline covers their development, indications, clinical trial results, adverse effects, and pharmacology/metabolism. Retinoids have been described historically and functionally in the context of interaction with their nuclear receptors—retinoic acid receptors (RARs) and retinoid X receptors (RXRs)—in inducing gene transcription. RAR‐selective retinoids or their prodrugs include first‐generation all‐ trans ‐retinoic acid (tretinoin) and its 13‐ cis isomer (isotretinoin), and second‐generation acitretin and its ethyl ester (etretinate), both having an aromatic 2,3,6‐trimethyl‐4‐methoxyphenyl terminus. Third‐generation more aromatic analogs include ethyl ester tazarotene (Tazorac®) and adapalene (Differin®), both selective for RAR subtypes β and γ, and RARα‐selective pipeline candidates Am80 and NRX 195183, which are in clinical trials. RAR and RXR transcriptional panagonist 9‐ cis ‐retinoic acid is next and is followed by RXR‐selective bexarotene (Targretin™) and two RXR‐selective clinical trial candidates, 9cUAB and NRX 194204. The fourth generation includes three compounds that may have applications in the treatment or prevention of cancer. While originally considered as retinoids, such as N ‐(4‐hydroxyphenyl) retinamide, or as retinoid‐related or derived, such as ST1926 (AHPC) and SHetA2, they subsequently were found to function independently of the RARs and RXRs in inhibiting cancer cell proliferation and inducing apoptosis.

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A Novel Atypical Retinoid Endowed with Proapoptotic and Antitumor Activity

Cited by 59 publications

References 6 publications

Induction of apoptosis and stress response in ovarian carcinoma cell lines treated with ST1926, an atypical retinoid

Induction of apoptosis and stress response in ovarian carcinoma cell lines treated with ST1926, an atypical retinoid

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

Retinoids

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