Resveratrol sensitizes breast cancer to PARP inhibitor, talazoparib through dual inhibition of AKT and autophagy flux

Bellare, Ganesh Pai; Patro, Birija Sankar

doi:10.1016/j.bcp.2022.115024

Cited by 25 publications

(21 citation statements)

References 63 publications

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“…Recently, a natural compound, resveratrol was reported to inhibit Akt activation and autophagy flux to impair HRmediated DSB-repair in breast cancer cells [31]. Therefore, we asked whether TMZ would further enhance the activity of the PI3K/Akt pathway in GBM cells.…”

Section: Resultsmentioning

confidence: 97%

“…PI3K was reported to preserve HR-steady state, and Akt activation could assist DSB repair to promote cell proliferation through upregulation of CDK inhibitor p21 and inhibition of DNA damage [ 28 – 30 ]. Recently, a natural compound, resveratrol was reported to inhibit Akt activation and autophagy flux to impair HR-mediated DSB-repair in breast cancer cells [ 31 ]. Therefore, we asked whether TMZ would further enhance the activity of the PI3K/Akt pathway in GBM cells.…”

Section: Resultsmentioning

confidence: 99%

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ZSTK474 Sensitizes Glioblastoma to Temozolomide by Blocking Homologous Recombination Repair

Jiao

Zhu

Shao

et al. 2022

BioMed Research International

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Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Temozolomide (TMZ) is used as the standard chemotherapeutic agent for GBM but with limited success, and treatment failure is mainly due to tumor resistance. One of the leading causes of TMZ resistance is the upregulation of the DNA repair mechanism. Therefore, targeting the DNA damage response (DDR) is proposed to be an effective strategy to sensitize tumor cells to TMZ. In the present study, we demonstrated that the combined use of the PI3K inhibitor ZSTK474 and TMZ showed synergetic anticancer effects on human GBM cells in vitro and in vivo. The combination treatment led to significantly increased cell apoptosis and DNA double strand breaks (DSBs). In addition, a mechanistic study indicated that TMZ enhanced the homologous recombination (HR) repair efficiency in GBM cells, while ZSTK474 impaired HR repair by blocking the phosphorylation of ATM and the expression of BRCA1/2 and Rad51, thereby sensitizing GBM cells to TMZ. Moreover, TMZ activated the PI3K signaling pathway through upregulation of the PI3K catalytic subunits p110α and p110β and the phosphorylation of Akt. Meanwhile, ZSTK474 blocked the activity of the PI3K/Akt pathway. Taken together, our findings suggested that the combination of ZSTK474 and TMZ might be a potential therapeutic option for GBM.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

ZSTK474 Sensitizes Glioblastoma to Temozolomide by Blocking Homologous Recombination Repair

Jiao

Zhu

Shao

et al. 2022

BioMed Research International

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“…RSV can be considered an anti-cancer agent (47) with potential use for cancer therapy (2, 51) and prevention (1) since it affects a variety of cancer stages from initiation and promotion to progression by acting on the diverse signal-transduction pathways that control cell growth and division, inflammation, apoptosis, metastasis, and angiogenesis [reviewed in (2)]. In addition, RSV can reverse multidrug resistance in cancer cells, and, when used in combination with clinically used drugs, it can sensitize cancer cells to standard chemotherapeutic agents (2,(52)(53)(54). This effect depends on the dose and tissue (55).…”

Section: Discussionmentioning

confidence: 99%

Resveratrol enhances A1 and hinders A2A adenosine receptors signaling in both HeLa and SH-SY5Y cells: Potential mechanism of its antitumoral action

Muñoz-López

Sánchez-Melgar²,

Martı́n³

et al. 2022

Front. Endocrinol.

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Despite great efforts, effective treatment against cancer has not yet been found. However, natural compounds such as the polyphenol resveratrol have emerged as promising preventive agent in cancer therapy. The mode of action of resveratrol is still poorly understood, but it can modulate many signaling pathways related to the initiation and progression of cancer. Adenosinergic signaling may be involved in the antitumoral action of resveratrol since resveratrol binds to the orthosteric binding site of adenosine A2A receptors and acts as a non-selective agonist for adenosine receptors. In the present study, we measured the impact of resveratrol treatment on different adenosinergic pathway components (i.e. adenosine receptors levels, 5’-nucleotidase, adenosine deaminase, and adenylyl cyclase activities, protein kinase A levels, intracellular adenosine and other related metabolites levels) and cell viability and proliferation in HeLa and SH-SY5Y cell lines. Results revealed changes leading to turning off cAMP signaling such as decreased levels of A2A receptors and reduced adenylyl cyclase activation, increased levels of A1 receptors and increased adenylyl cyclase inhibition, and lower levels of PKA. All these changes could contribute to the antitumoral action of resveratrol. Interestingly, these effects were almost identical in HeLa and SH-SY5Y cells suggesting that resveratrol enhances A1 and hinders A2A adenosine receptors signaling as part of a potential mechanism of antitumoral action.

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“…It is worth mentioning here that in contrast to combinations with IR, BMN673 treatment applied as a monotherapy resulted in elevated levels of 53BP1 foci [ 39 , 148 , 149 , 150 ], indicating enhanced c-NHEJ activity in this setting. More studies are warranted to elucidate the impact of BMN673 on c-NHEJ, either when used as a monotherapy or when combined with IR.…”

Section: Shift Of Balance To Error-prone Dsb Repair Pathways Is Likel...mentioning

confidence: 99%

BMN673 Is a PARP Inhibitor with Unique Radiosensitizing Properties: Mechanisms and Potential in Radiation Therapy

Soni

Lin

Mladenov

et al. 2022

Cancers

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BMN673 is a relatively new PARP inhibitor (PARPi) that exhibits superior efficacy in vitro compared to olaparib and other clinically relevant PARPi. BMN673, similar to most clinical PARPi, inhibits the catalytic activities of PARP-1 and PARP-2 and shows impressive anticancer potential as monotherapy in several pre-clinical and clinical studies. Tumor resistance to PARPi poses a significant challenge in the clinic. Thus, combining PARPi with other treatment modalities, such as radiotherapy (RT), is being actively pursued to overcome such resistance. However, the modest to intermediate radiosensitization exerted by olaparib, rucaparib, and veliparib, limits the rationale and the scope of such combinations. The recently reported strong radiosensitizing potential of BMN673 forecasts a paradigm shift on this front. Evidence accumulates that BMN673 may radiosensitize via unique mechanisms causing profound shifts in the balance among DNA double-strand break (DSB) repair pathways. According to one of the emerging models, BMN673 strongly inhibits classical non-homologous end-joining (c-NHEJ) and increases reciprocally and profoundly DSB end-resection, enhancing error-prone DSB processing that robustly potentiates cell killing. In this review, we outline and summarize the work that helped to formulate this model of BMN673 action on DSB repair, analyze the causes of radiosensitization and discuss its potential as a radiosensitizer in the clinic. Finally, we highlight strategies for combining BMN673 with other inhibitors of DNA damage response for further improvements.

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Resveratrol sensitizes breast cancer to PARP inhibitor, talazoparib through dual inhibition of AKT and autophagy flux

Cited by 25 publications

References 63 publications

ZSTK474 Sensitizes Glioblastoma to Temozolomide by Blocking Homologous Recombination Repair

ZSTK474 Sensitizes Glioblastoma to Temozolomide by Blocking Homologous Recombination Repair

Resveratrol enhances A1 and hinders A2A adenosine receptors signaling in both HeLa and SH-SY5Y cells: Potential mechanism of its antitumoral action

BMN673 Is a PARP Inhibitor with Unique Radiosensitizing Properties: Mechanisms and Potential in Radiation Therapy

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