Quinazolinedione SIRT6 inhibitors sensitize cancer cells to chemotherapeutics

Sociali, Giovanna; Galeno, Lauretta; Parenti, Marco; Grozio, Alessia; Bauer, Inga; Passalacqua, Mario; Boero, Silvia; Donadini, Alessandra; Millo, Enrico; Bellotti, Marta; Sturla, Laura; Damonte, Patrizia; Puddu, Alessandra; Ferroni, Claudia; Varchi, Greta; Franceschi, Claudio; Ballestrero, Alberto; Poggi, Alessandro; Bruzzone, Santina; Nencioni, Alessio; Río, Alberto Del

doi:10.1016/j.ejmech.2015.08.024

Cited by 67 publications

(63 citation statements)

References 32 publications

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“…In conclusion, based on these early ADME results, compounds 1 and 2 were considered to be early leading candidates for our in vivo study. Ultimately, given its stronger in vitro activity in increasing cell glucose uptake compared to compound 2, as detected both in L6 skeletal muscle cells and in BxPC3 pancreatic cells (18), compound 1 was selected for our in vivo study. The cytotoxicity of compound 1 was evaluated on a liver hepatocellular cell line, HepG2; addition of up to 200 μM of compound 1 did not significantly affect cell viability for 72 h (cell viability, 99.1 ± 0.6, 98.4 ± 0.3, and 97.4 ± 1.7% in cells treated with 25, 100, or 200 μM, respectively, relative to untreated cells).…”

Section: Resultsmentioning

confidence: 99%

Pharmacological Sirt6 inhibition improves glucose tolerance in a type 2 diabetes mouse model

et al. 2017

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Sirtuin 6 (SIRT6) is a sirtuin family member involved in a wide range of physiologic and disease processes, including cancer and glucose homeostasis. Based on the roles played by SIRT6 in different organs, including its ability to repress the expression of glucose transporters and glycolytic enzymes, inhibiting SIRT6 has been proposed as an approach for treating type 2 diabetes mellitus (T2DM). However, so far, the lack of small-molecule Sirt6 inhibitors has hampered the conduct of studies to assess the viability of this strategy. We took advantage of a recently identified SIRT6 inhibitor, compound 1, to study the effect of pharmacological Sirt6 inhibition in a mouse model of T2DM ( in high-fat-diet-fed animals). The administration of the Sirt6 inhibitor for 10 d was well tolerated and improved oral glucose tolerance, it increased the expression of the glucose transporters GLUT1 and -4 in the muscle and enhanced the activity of the glycolytic pathway. Sirt6 inhibition also resulted in reduced insulin, triglycerides, and cholesterol levels in plasma. This study represents the first study of a SIRT6 inhibitor and provides the proof-of-concept that targeting SIRT6 may be a viable strategy for improving glycemic control in T2DM.-Sociali, G., Magnone, M., Ravera, S., Damonte, P., Vigliarolo, T., Von Holtey, M., Vellone, V. G., Millo, E., Caffa, I., Cea, M., Parenti, M. D., Del Rio, A., Murone, M., Mostoslavsky, R., Grozio, A., Nencioni, A., Bruzzone S. Pharmacological Sirt6 inhibition improves glucose tolerance in a type 2 diabetes mouse model.

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Section: Resultsmentioning

confidence: 99%

Pharmacological Sirt6 inhibition improves glucose tolerance in a type 2 diabetes mouse model

et al. 2017

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“…2×10 4 OCI-AML2 (E) and primary AML (F) cells/well were plated in 96-well plates and incubated for 72 h with (w) / or without (w/o) DNR/ARA-C (at the indicated concentration) w / or w/o compound 1, as in Sociali et al . 34 Thereafter, dead cells were detected by propidium iodide staining and flow cytometry. *0.04< P <0.01; **0.009< P <0.001; ***<0.0001.…”

Section: Resultsmentioning

confidence: 99%

Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells’ vulnerability to DNA-damaging agents

et al. 2017

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Genomic instability plays a pathological role in various malignancies, including acute myeloid leukemia (AML), and thus represents a potential therapeutic target. Recent studies demonstrate that SIRT6, a NAD+-dependent nuclear deacetylase, functions as genome-guardian by preserving DNA integrity in different tumor cells. Here, we demonstrate that also CD34+ blasts from AML patients show ongoing DNA damage and SIRT6 overexpression. Indeed, we identified a poor-prognostic subset of patients, with widespread instability, which relies on SIRT6 to compensate for DNA-replication stress. As a result, SIRT6 depletion compromises the ability of leukemia cells to repair DNA double-strand breaks that, in turn, increases their sensitivity to daunorubicin and Ara-C, both in vitro and in vivo. In contrast, low SIRT6 levels observed in normal CD34+ hematopoietic progenitors explain their weaker sensitivity to genotoxic stress. Intriguingly, we have identified DNA-PKcs and CtIP deacetylation as crucial for SIRT6-mediated DNA repair. Together, our data suggest that inactivation of SIRT6 in leukemia cells leads to disruption of DNA-repair mechanisms, genomic instability and aggressive AML. This synthetic lethal approach, enhancing DNA damage while concomitantly blocking repair responses, provides the rationale for the clinical evaluation of SIRT6 modulators in the treatment of leukemia.

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“…However, the oncogenic role of SIRT6 has also been described: Sociali et al identified that the inhibition of SIRT6 sensitizes pancreatic cancer cells to chemotherapeutics (20). In addition, SIRT6 was also demonstrated to prevent hepatocellular carcinoma cell apoptosis by suppressing B cell lymphoma 2-associated X protein expression (21).…”

Section: Discussionmentioning

confidence: 99%

SIRT6 inhibits colorectal cancer stem cell proliferation by targeting CDC25A

Liu

et al. 2018

Oncol Lett

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Abstract. Silent information regulator 6 (SIRT6) is broadly considered as a tumor suppressor due to its function in the suppression of oncogene expression. However, the role of SIRT6 in colorectal cancer stem cells (CSCs) remains uncharacterized. In the present study, it was demonstrated that SIRT6 expression was reduced in colorectal CSCs. Overexpression of SIRT6 in colorectal CSCs did not induce cell apoptosis. However, SIRT6 significantly inhibited cell proliferation, colony formation and induced G0/G1 phase arrest in colorectal CSCs. In addition, SIRT6 repressed the expression of cell division cycle 25A (CDC25A), an oncogenic phosphatase. Chromatin immunoprecipitation experiments indicated that SIRT6 directly bound to the CDC25A promoter and decreased the acetylation level of histone H3 lysine 9. Altogether, these data indicated that SIRT6 inhibits colorectal cancer stem cell proliferation by targeting CDC25A.

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Quinazolinedione SIRT6 inhibitors sensitize cancer cells to chemotherapeutics

Cited by 67 publications

References 32 publications

Pharmacological Sirt6 inhibition improves glucose tolerance in a type 2 diabetes mouse model

Pharmacological Sirt6 inhibition improves glucose tolerance in a type 2 diabetes mouse model

Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells’ vulnerability to DNA-damaging agents

SIRT6 inhibits colorectal cancer stem cell proliferation by targeting CDC25A

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