6-Thioguanine and Its Analogs Promote Apoptosis of Castration-Resistant Prostate Cancer Cells in a BRCA2-Dependent Manner

Laera, Luna; Guaragnella, Nicoletta; Giannattasio, Sergio; Moro, Loredana

doi:10.3390/cancers11070945

Cited by 6 publications

(6 citation statements)

References 48 publications

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“…The compound had no detrimental effects on HUVEC viability under normal or high glucose conditions at all the doses tested. This is in line with the previous evidence reporting 6TG as able to promote apoptosis only in cancer cells ( Laera et al, 2019 ; Li et al, 2020 ). In particular, 5 µM 6TG significantly increased the cell viability of HUVECs exposed to high glucose and also reduced their vasculogenic activity, confirming its anti-angiogenic effects previously reported in endothelial cells or the chick embryo chorioallantoic membrane, as well as in AML patients showing a reduced bone marrow microvessel density when treated with 6TG ( Padró et al, 2000 ; Presta et al, 2002 ; Dean, 2012 ).…”

Section: Discussionsupporting

confidence: 93%

Ocular pharmacological and biochemical profiles of 6-thioguanine: a drug repurposing study

Trotta,

Gesualdo,

Lepre

et al. 2024

Front. Pharmacol.

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Introduction:The purine analog 6-thioguanine (6TG), an old drug approved in the 60s to treat acute myeloid leukemia (AML), was tested in the diabetic retinopathy (DR) experimental in vivo setting along with a molecular modeling approach.Methods:A computational analysis was performed to investigate the interaction of 6TG with MC1R and MC5R. This was confirmed in human umbilical vein endothelial cells (HUVECs) exposed to high glucose (25 mM) for 24 h. Cell viability in HUVECs exposed to high glucose and treated with 6TG (0.05–0.5–5 µM) was performed. To assess tube formation, HUVECs were treated for 24 h with 6TG 5 µM and AGRP (0.5–1–5 µM) or PG20N (0.5–1–5–10 µM), which are MC1R and MC5R antagonists, respectively. For the in vivo DR setting, diabetes was induced in C57BL/6J mice through a single streptozotocin (STZ) injection. After 2, 6, and 10 weeks, diabetic and control mice received 6TG intravitreally (0.5–1–2.5 mg/kg) alone or in combination with AGRP or PG20N. Fluorescein angiography (FA) was performed after 4 and 14 weeks after the onset of diabetes. After 14 weeks, mice were euthanized, and immunohistochemical analysis was performed to assess retinal levels of CD34, a marker of endothelial progenitor cell formation during neo-angiogenesis.Results:The computational analysis evidenced a more stable binding of 6TG binding at MC5R than MC1R. This was confirmed by the tube formation assay in HUVECs exposed to high glucose. Indeed, the anti-angiogenic activity of 6TG was eradicated by a higher dose of the MC5R antagonist PG20N (10 µM) compared to the MC1R antagonist AGRP (5 µM). The retinal anti-angiogenic effect of 6TG was evident also in diabetic mice, showing a reduction in retinal vascular alterations by FA analysis. This effect was not observed in diabetic mice receiving 6TG in combination with AGRP or PG20N. Accordingly, retinal CD34 staining was reduced in diabetic mice treated with 6TG. Conversely, it was not decreased in diabetic mice receiving 6TG combined with AGRP or PG20N.Conclusion:6TG evidenced a marked anti-angiogenic activity in HUVECs exposed to high glucose and in mice with DR. This seems to be mediated by MC1R and MC5R retinal receptors.

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Section: Discussionsupporting

confidence: 93%

Ocular pharmacological and biochemical profiles of 6-thioguanine: a drug repurposing study

Trotta,

Gesualdo,

Lepre

et al. 2024

Front. Pharmacol.

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“…In addition, TG has been tested in both non-small cell lung cancer [45] and recurrent small cell lung cancer [46] but no clinical response was observed in these patients. Recently, interest in TG has risen again, promising preliminary results were found in prostate cancer [47]. Furthermore, TG was widely investigated for the treatment of glioma and showed positive results in patients who failed conventional chemoradiotherapy [48][49][50][51][52][53][54][55].…”

Section: Oncology and Hematologymentioning

confidence: 99%

The continuous rediscovery and the benefit–risk ratio of thioguanine, a comprehensive review

Bayoumy

Simsek

Seinen

et al. 2020

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: In the 1950s, thioguanine (TG), a thiopurine-derivative together with azathioprine (AZA) and mercaptopurine (MP), were developed for the treatment of childhood leukemia. Over the years, the use of TG was also explored for other, mainly immune-mediated and inflammatory, diseases such as in the field of dermatology and rheumatology (e.g. psoriasis, systemic lupus erythematosus (SLE)) and gastroenterology and hepatology (e.g. inflammatory bowel diseases (IBD), autoimmune hepatitis).Areas covered: This review provides a comprehensive overview of all the clinical uses of TG and describes its mechanism of action, pharmacokinetic/pharmacodynamic features, and toxicity. Expert opinion: Thioguanine has shown beneficial clinical effects in hematological (particularly leukemia) and several immune-inflammatory diseases including psoriasis, SLE, polycythemia vera, Churg-Strauss syndrome, IBD, collagenous sprue, refractory celiac disease, and autoimmune hepatitis. Thioguanine is not effective in treating solid-cancers. At relatively low dosages, i.e. 0.2-0.3mg/kg/day or 20 mg/day, TG has a favorable risk-benefit ratio and is a safe and effective drug in the long-term treatment of amongst other IBD patients. Thioguanine toxicity, especially myelotoxicity, and hepatotoxicity, including nodular regenerative hyperplasia (NRH) of the liver, is limited when dosed adequately. The occurrence of NRH appears dose-dependent and has been especially described during high dose TG above 40 mg/day.

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“…The loss of MTAP expression has been linked to a tumor-promoting effect in multiple cancers, and MTAP may serve as a tumor suppressor ( 28 – 30 ). For example, in 2021, Han et al.…”

Section: Discussionmentioning

confidence: 99%

“…The loss of MTAP expression has been linked to a tumorpromoting effect in multiple cancers, and MTAP may serve as a tumor suppressor (28)(29)(30). For example, in 2021, Han et al found that 9p21 loss, normally CDKN2A (13.5%) and MTAP (9.3%), confers a cold tumor immune microenvironment, poor clinical outcomes, and primary resistance to immune checkpoint therapy for cancers (31).…”

Section: Discussionmentioning

confidence: 99%

Genomic alteration of MTAP/CDKN2A predicts sarcomatoid differentiation and poor prognosis and modulates response to immune checkpoint blockade in renal cell carcinoma

Anwaier

Liu

et al. 2022

Front. Immunol.

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Sarcomatoid differentiation is a highly aggressive pathological characteristic of renal cell carcinoma (RCC) and is characterized by susceptibility to progression and extremely poor prognosis. In this study, we included all genomic alteration events that led to a loss of protein function of MTAP and CDKN2A, and enrolled 5,307 RCC patients with genomic sequencing data from Western and Chinese cohorts. Notably, MTAP/CDKN2AMUT occurred in the Chinese population ~2 times more frequently than in the Western cohort and showed significant co-mutation trends. We found significantly higher proportions of sarcomatoid-positive patients with MTAPMUT or CDKN2AMUT compared with MTAP/CDKN2A wild-type (WT) patients (P < 0.001). Of the 574 RCC samples from the FUSCC cohort and 3,563 RCC samples from 17 independent cohorts, the MTAP/CDKN2AMUT significantly predicted extremely poor outcomes (P < 0.0001). The Western cohort suggested a concordant relationship between MTAP/CDKN2AMUT and sarcomatoid differentiation in RCC. Moreover, although MTAP/CDKN2AMUT RCC may be insensitive to targeted therapy, the high degree of tumor heterogeneity and higher PD-L1 and CXCL13 expression characterizations reflected that MTAP/CDKN2A-deficient features could benefit from immunotherapy for patients with RCC. This study utilized RCC samples from large-scale, global, multicenter sequencing cohorts and first proved that MTAP/CDKN2A deficiency significantly correlates with sarcomatoid differentiation in RCC and predicts aggressive progression, poor prognosis, and primary resistance to targeted therapy and potential favorable responses to immune checkpoint blockade. Unlike conventional targeted therapies, emerging drugs such as immunotherapies or synthetic lethal PRMT5 inhibitors may become novel therapeutic options for patients with MTAP/CDKN2AMUT RCC.

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6-Thioguanine and Its Analogs Promote Apoptosis of Castration-Resistant Prostate Cancer Cells in a BRCA2-Dependent Manner

Cited by 6 publications

References 48 publications

Ocular pharmacological and biochemical profiles of 6-thioguanine: a drug repurposing study

Ocular pharmacological and biochemical profiles of 6-thioguanine: a drug repurposing study

The continuous rediscovery and the benefit–risk ratio of thioguanine, a comprehensive review

Genomic alteration of MTAP/CDKN2A predicts sarcomatoid differentiation and poor prognosis and modulates response to immune checkpoint blockade in renal cell carcinoma

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