Comparing PI3K/Akt Inhibitors Used in Ovarian Cancer Treatment

Wu, Yi Hui; Huang, Yu Fang; Chen, Chia Ling; Huang, Chia-Yen; Chou, Cheng Yang

doi:10.3389/fphar.2020.00206

Cited by 31 publications

(24 citation statements)

References 39 publications

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“…This highlights the current need for novel treatments. Therefore, PI3 kinase inhibitors are now emerging with the potential for the treatment of cancers [ 15 , 24 , 25 , 26 ]. There are few reports on the use of LY294002 in investigations of gliomas.…”

Section: Discussionmentioning

confidence: 99%

Involvement of PI3K Pathway in Glioma Cell Resistance to Temozolomide Treatment

Zając

Sumorek-Wiadro

Langner

et al. 2021

IJMS

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The aim of the study was to investigate the anticancer potential of LY294002 (PI3K inhibitor) and temozolomide using glioblastoma multiforme (T98G) and anaplastic astrocytoma (MOGGCCM) cells. Apoptosis, autophagy, necrosis, and granules in the cytoplasm were identified microscopically (fluorescence and electron microscopes). The mitochondrial membrane potential was studied by flow cytometry. The activity of caspases 3, 8, and 9 and Akt was evaluated fluorometrically, while the expression of Beclin 1, PI3K, Akt, mTOR, caspase 12, and Hsp27 was determined by immunoblotting. SiRNA was used to block Hsp27 and PI3K expression. Cell migration and localization of Hsp27 were tested with the wound healing assay and immunocytochemistry, respectively. LY294002 effectively diminished the migratory potential and increased programmed death of T98G and MOGGCCM. Autophagy was dominant in MOGGCCM, while apoptosis was dominant in T98G. LY294002 with temozolomide did not potentiate cell death but redirected autophagy toward apoptosis, which was correlated with ER stress. A similar effect was observed after blocking PI3K expression with siRNA. Transfection with Hsp27 siRNA significantly increased apoptosis related to ER stress. Our results indicate that inhibition of the PI3K/Akt/mTOR pathway sensitizes glioma cells to apoptosis upon temozolomide treatment, which was correlated with ER stress. Hsp27 increases the resistance of glioma cells to cell death upon temozolomide treatment.

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Section: Discussionmentioning

confidence: 99%

Involvement of PI3K Pathway in Glioma Cell Resistance to Temozolomide Treatment

Zając

Sumorek-Wiadro

Langner

et al. 2021

IJMS

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“…Instead, the use of inhibitors targeting different aspects of the pathway has shown success. Multiple studies have utilized specific inhibitors of the pathway (AZD8835, AZD8186, and D-11688) and silencing RNA to increase the number of apoptotic cells in a dose-dependent manner, reduce anchorage-independent growth, and sensitize resistant cells to chemotherapy [ 251 , 252 , 253 ]. Interestingly, the combination of a PI3K pathway inhibitor with a BCL-2 family inhibitor showed synergistic effects in increasing cell death [ 254 , 255 ].…”

Section: Taxane Resistance In Ovarian Cancermentioning

confidence: 99%

Mechanisms of Taxane Resistance

Maloney

Hoover

Morejon-Lasso

et al. 2020

Cancers

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The taxane family of chemotherapy drugs has been used to treat a variety of mostly epithelial-derived tumors and remain the first-line treatment for some cancers. Despite the improved survival time and reduction of tumor size observed in some patients, many have no response to the drugs or develop resistance over time. Taxane resistance is multi-faceted and involves multiple pathways in proliferation, apoptosis, metabolism, and the transport of foreign substances. In this review, we dive deeper into hypothesized resistance mechanisms from research during the last decade, with a focus on the cancer types that use taxanes as first-line treatment but frequently develop resistance to them. Furthermore, we will discuss current clinical inhibitors and those yet to be approved that target key pathways or proteins and aim to reverse resistance in combination with taxanes or individually. Lastly, we will highlight taxane response biomarkers, specific genes with monitored expression and correlated with response to taxanes, mentioning those currently being used and those that should be adopted. The future directions of taxanes involve more personalized approaches to treatment by tailoring drug–inhibitor combinations or alternatives depending on levels of resistance biomarkers. We hope that this review will identify gaps in knowledge surrounding taxane resistance that future research or clinical trials can overcome.

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“…These encouraging data, corroborated by our in vitro analysis, pave the way to test the concept of AKT inhibition in PeCa as a mono or combination therapy. In particular, taking into account the role of AKT in cisplatin resistance in different cancers as well as the observed sensitization of cisplatin-sensitive and -resistant ovarian cancer cells by adding capivasertib, combining AKT inhibitors with cisplatin as the hub of the systemic therapy for metastasized PeCa presents an intriguing novel therapeutic option [ 34 , 35 , 43 ]. Whether the presence of activating genomic alterations of the PIK3CA/AKT1/PTEN pathway represents a clinically relevant predictive factor for selecting PeCa patients for AKT inhibition has to be further elucidated.…”

Section: Discussionmentioning

confidence: 99%

Assessment of PI3K/mTOR/AKT Pathway Elements to Serve as Biomarkers and Therapeutic Targets in Penile Cancer

Thomas¹,

Reetz²,

Stenzel³

et al. 2021

Cancers

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The PI3K/mTOR/AKT pathway might represent an intriguing option for treatment of penile cancer (PeCa). We aimed to assess whether members of this pathway might serve as biomarkers and targets for systemic therapy. Tissue of primary cancer from treatment-naïve PeCa patients was used for tissue microarray analysis. Immunohistochemical staining was performed with antibodies against AKT, pAKT, mTOR, pmTOR, pS6, pPRAS, p4EBP1, S6K1 and pp70S6K. Protein expression was correlated with clinicopathological characteristics as well as overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS) and metastasis-free survival (MFS). AKT inhibition was tested in two primarily established, treatment-naïve PeCa cell lines by treatment with capivasertib and analysis of cell viability and chemotaxis. A total of 76 patients surgically treated for invasive PeCa were included. Higher expression of AKT was significantly more prevalent in high-grade tumors and predictive of DSS and OS in the Kaplan–Meier analysis, and an independent predictor of worse OS and DSS in the multivariate regression analysis. Treatment with pan-AKT inhibitor capivasertib in PeCa cell lines induced a significant downregulation of both total AKT and pAKT as well as decreased cell viability and chemotaxis. Selected protein candidates of the mTOR/AKT signaling pathway demonstrate association with histological and survival parameters of PeCa patients, whereas AKT appears to be the most promising one.

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Comparing PI3K/Akt Inhibitors Used in Ovarian Cancer Treatment

Cited by 31 publications

References 39 publications

Involvement of PI3K Pathway in Glioma Cell Resistance to Temozolomide Treatment

Involvement of PI3K Pathway in Glioma Cell Resistance to Temozolomide Treatment

Mechanisms of Taxane Resistance

Assessment of PI3K/mTOR/AKT Pathway Elements to Serve as Biomarkers and Therapeutic Targets in Penile Cancer

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