Targeting the PI3K pathway and DNA damage response as a therapeutic strategy in ovarian cancer

Huang, Tzu Ting; Lampert, Erika J.; Coots, Cynthia; Lee, Jungmin

doi:10.1016/j.ctrv.2020.102021

Cited by 116 publications

(93 citation statements)

References 97 publications

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“…There is ongoing research evaluating the combination of PARP inhibitors with other agents to extend the therapeutic potential of these inhibitors beyond tumors with mutations of BRCA or other HR deficiencies. As the PI3K/Akt/mTOR pathway contributes to the DDR, combination of PI3K/Akt/mTOR inhibitors with PARP inhibitors was exploited in several solid tumor models [320,321]. Inhibition of the PI3K/Akt/mTOR pathway in ovarian, breast, and prostate cancers revealed impaired expression of BRCA1/2 and reduced cellular capacity to conduct HR [322][323][324][325].…”

Section: Pi3k/akt/mtor Inhibitors In Combination With Dna Repair Inhimentioning

confidence: 99%

Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

Darici

Alkhaldi

Horne

et al. 2020

JCM

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Acute myeloid leukemia (AML) is a highly heterogeneous hematopoietic malignancy characterized by excessive proliferation and accumulation of immature myeloid blasts in the bone marrow. AML has a very poor 5-year survival rate of just 16% in the UK; hence, more efficacious, tolerable, and targeted therapy is required. Persistent leukemia stem cell (LSC) populations underlie patient relapse and development of resistance to therapy. Identification of critical oncogenic signaling pathways in AML LSC may provide new avenues for novel therapeutic strategies. The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathway, is often hyperactivated in AML, required to sustain the oncogenic potential of LSCs. Growing evidence suggests that targeting key components of this pathway may represent an effective treatment to kill AML LSCs. Despite this, accruing significant body of scientific knowledge, PI3K/Akt/mTOR inhibitors have not translated into clinical practice. In this article, we review the laboratory-based evidence of the critical role of PI3K/Akt/mTOR pathway in AML, and outcomes from current clinical studies using PI3K/Akt/mTOR inhibitors. Based on these results, we discuss the putative mechanisms of resistance to PI3K/Akt/mTOR inhibition, offering rationale for potential candidate combination therapies incorporating PI3K/Akt/mTOR inhibitors for precision medicine in AML.

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Section: Pi3k/akt/mtor Inhibitors In Combination With Dna Repair Inhimentioning

confidence: 99%

Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

Darici

Alkhaldi

Horne

et al. 2020

JCM

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“…The PI3K/AKT/mTOR pathway was involved in many human cancers, including OC, which induced the apoptotic response through its ability to interplay with a great quantity of major genes in the apoptosis. 46 Once this pathway was activated, it would initiate phosphorylation of transcription factors, then upregulate the expression levels of anti-apoptotic genes and downregulate levels of proapoptotic proteins. Thus, an inhibitor targeted on the PI3K/ AKT/mTOR pathway might also induced apoptosis.…”

Section: Molecular Docking Analysismentioning

confidence: 99%

<p>Anti-Tumor Xanthones from <em>Garcinia nujiangensis</em> Suppress Proliferation, and Induce Apoptosis via PARP, PI3K/AKT/mTOR, and MAPK/ERK Signaling Pathways in Human Ovarian Cancers Cells</p>

Tang¹,

Lu²,

Xia³

2020

DDDT

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Background: Ovarian cancer (OC) is a serious public health concern in the world. It is important to develop novel drugs to inhibit OC. Purpose: This study investigated the isolation, elucidation, efficiency, molecular docking, and pharmaceutical mechanisms of xanthones isolated from Garcinia nujiangensis. Methods: Xanthones were isolated, and purified by different chromatography, including silica gel, reversed-phase silica gel (ODS-C 18), and semipreparative HPLC, then identified by analysis of their spectral data. Three xanthones were estimated for their efficiency on the human OC cells HEY and ES-2. 2 was found to be the most potent cytotoxic xanthones of those tested. Further, its mechanisms of action were explored by molecular docking, cell apoptosis, and Western blotting analysis. Results: Bioassay-guided fractionation of the fruits of Garcinia nujiangensis led to the separation of a new xanthone named nujiangexanthone G (1) and two known xanthones. Among these, isojacareubin (2) exhibited the most potent cytotoxic compound against the HEY and ES-2 cell lines. The analysis of Western blot suggested that 2 inhibited OC via regulating the PARP, PI3K/ AKT/mTOR, and ERK/MAPK signal pathways in the HEY cell lines. Conclusion: In conclusion, isojacareubin (2) might be a potential drug for the treatment of OC.

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“…Previous studies showed hyperactivation of the phosphoinositol-3-kinases (PI3K), AKT, mTOR (PI3K/AKT) pathway in nearly 60% of patients with ovarian cancer. This pathway plays a significant role in cancer cell growth, cell survival, programming of metabolic, autophagy, regulation of transcription, and angiogenesis ( Ghoneum and Said, 2019 ; Huang et al, 2020b ). Activation of the PI3K pathway causes downstream Protein Kinase B (PKB) signaling activation.…”

Section: Introductionmentioning

confidence: 99%

Curcumin Nanoparticle Enhances the Anticancer Effect of Cisplatin by Inhibiting PI3K/AKT and JAK/STAT3 Pathway in Rat Ovarian Carcinoma Induced by DMBA

et al. 2021

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Cisplatin has been used for decades for the treatment of ovarian cancer. However, despite its potent anticancer effect, cisplatin’s efficacy as a single agent was inadequate in patients with advanced stage. Curcumin has been shown to sensitize cisplatin activity in several cancer models. However, the low bioavailability of curcumin has limited its anticancer potential. Hence, nano-formulation of curcumin was developed to increase its therapeutic efficacy in ovarian cancer. The objective of this study was to investigate the mechanism of curcumin nanoparticles given in combination with cisplatin in rat ovarian carcinoma induced by dimethylbenz(a)anthracene (DMBA). The administration of cisplatin and nanocurcumin resulted in a significant reduction in ovarian tumor volume and weight. Furthermore, there were reduction in expressions of Ki67, TGF-β, PI3K, and Akt phosphorylation. Co-treatment of cisplatin and nanocurcumin also reduced JAK expression, STAT3 phosphorylation, and reduced IL-6 concentrations. Altogether, nanocurcumin, given as a co-treatment with cisplatin has therapeutic potential in ovarian cancer models by inhibiting proliferation through downregulation of PI3K/Akt and JAK/STAT3 signaling pathways.

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Targeting the PI3K pathway and DNA damage response as a therapeutic strategy in ovarian cancer

Cited by 116 publications

References 97 publications

Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

<p>Anti-Tumor Xanthones from <em>Garcinia nujiangensis</em> Suppress Proliferation, and Induce Apoptosis via PARP, PI3K/AKT/mTOR, and MAPK/ERK Signaling Pathways in Human Ovarian Cancers Cells</p>

Curcumin Nanoparticle Enhances the Anticancer Effect of Cisplatin by Inhibiting PI3K/AKT and JAK/STAT3 Pathway in Rat Ovarian Carcinoma Induced by DMBA

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