Dual PI3K/mTOR inhibitor PKI-402 suppresses the growth of ovarian cancer cells by degradation of Mcl-1 through autophagy

Hu, Xin; Xia, Meihui; Wang, Jiabin; Yu, Huimei; Chai, Jiannan; Zhang, Zejun; Sun, Yupei; Su, Jing; Sun, Liankun

doi:10.1016/j.biopha.2020.110397

Cited by 31 publications

(20 citation statements)

References 38 publications

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“…We also demonstrated significant and prolonged attenuation of pAkt, pS6, and p4EBP-1 expression and antiproliferative properties of the PI3K/mTOR dual inhibitors in vitro. This is consistent with previous studies where PI3K/mTOR dual inhibitors showed antineoplastic properties in various cancer cell lines [58][59][60][61][62]. Despite the abundant supporting evidence for their antineoplastic properties, multiple clinical trials of PI3K/mTOR dual inhibitors reported unacceptable toxicity, resulting in the early termination of trials, including one phase II study in pNET [26,28,63,64].…”

Section: Discussionsupporting

confidence: 89%

PI3K/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic Neuroendocrine Tumors

Chow

Johnson

Chauhan

et al. 2021

Cells

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Patients with advanced-stage gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have a poor overall prognosis despite chemotherapy and radiotherapy (e.g., peptide receptor radionuclide therapy (PRRT)). Better treatment options are needed to improve disease regression and patient survival. The purpose of this study was to examine a new treatment strategy by combining PI3K/mTOR dual inhibition and radiotherapy. First, we assessed the efficacy of two PI3K/mTOR dual inhibitors, PF-04691502 and PKI-402, to inhibit pAkt and increase apoptosis in NET cell lines (BON and QGP-1) and patient-derived tumor spheroids as single agents or combined with radiotherapy (XRT). Treatment with PF-04691502 decreased pAkt (Ser473) expression for up to 72 h compared with the control; in contrast, decreased pAkt expression was noted for less than 24 h with PKI-402. Simultaneous treatment with PF-04691502 and XRT did not induce apoptosis in NET cells; however, the addition of PF-04691502 48 h after XRT significantly increased apoptosis compared to PF-04691502 or XRT treatment alone. Our results demonstrate that schedule-dependent administration of a PI3K/mTOR inhibitor, combined with XRT, can enhance cytotoxicity by promoting the radiosensitivity of NET cells. Moreover, our findings suggest that radiotherapy, in combination with timed PI3K/mTOR inhibition, may be a promising therapeutic regimen for patients with GEP-NET.

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Section: Discussionsupporting

confidence: 89%

PI3K/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic Neuroendocrine Tumors

Chow

Johnson

Chauhan

et al. 2021

Cells

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“…37 PKI-402, an inhibitor of the PI3K/mTOR pathway, has also been proven to promote autophagy and result in an imbalance of Bcl-2 family proteins in ovarian cancer. 38 Collectively, our current data show that the silencing of Circ-…”

Section: Discussionmentioning

confidence: 52%

“…In addition, the suppression of pleckstrin homology like domain family A member 2 in colorectal cancer contributes to enhanced cell apoptosis and autophagy by inactivating the PI3K/AKT/mTOR signaling pathway 37 . PKI‐402, an inhibitor of the PI3K/mTOR pathway, has also been proven to promote autophagy and result in an imbalance of Bcl‐2 family proteins in ovarian cancer 38 …”

Section: Discussionmentioning

confidence: 99%

The depletion of Circ‐PRKDC enhances autophagy and apoptosis in T‐cell acute lymphoblastic leukemia via microRNA‐653‐5p/Reelin mediation of the PI3K/AKT/mTOR signaling pathway

Zhang

Fang

et al. 2021

The Kaohsiung J of Med Scie

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A range of circular (Circ) RNAs have been demonstrated to be of therapeutic significance for the treatment of acute lymphoblastic leukemia (ALL). Here, we investigated the mechanisms underlying the action of Circ-PRKDC and the microRNA-653-5p/ Reelin (miR-653-5p/RELN) axis in T-cell ALL (T-ALL).Clinical specimens were obtained from patients with T-ALL (n = 39) and healthy controls (n = 30). In each specimen, we determined the expression levels of Circ-PRKDC, miR-653-5p, and RELN. Human T-ALL cells (Jurkat) were transfected with Circ-PRKDC-or miR-653-5p-related sequences to investigate cell proliferation, apoptosis, and autophagy. We also determined the levels of Circ-PRKDC, miR-653-5p, RELN, and signaling proteins related to phosphoinositide 3-kinase (PI3K), AKT, and mammalian target of rapamycin (mTOR). Finally, we decoded the interactions between Circ-PRKDC, miR-653-5p, and RELN. The expression levels of Circ-PRKDC and RELN were upregulated in T-ALL tissues and cells while the levels of miR-653-5p were downregulated. Thereafter, then silencing of Circ-PRKDC, or the enforced expression of miR-653-5p, repressed the expression of RELN and the activation of the PI3K/AKT/mTOR signaling pathway, thus enhancing cell autophagy and apoptosis, and disrupting cell proliferation. Circ-PRKDC acted a sponge for miR-653-5p while miR-653-5p targeted RELN. The knockdown of miR-653-5p abrogated the silencing of Circ-PRKDCinduced effects in T-ALL cells. The depletion of Circ-PRKDC elevated miR-653-5p to silence RELN-mediated PI3K/AKT/mTOR signaling activation, thereby enhancing autophagy and apoptosis in T-ALL cells.

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“…These results strongly indicate that PKI-402 is a possible drug to treat osteolysis caused by breast cancer. ( Hu et al, 2020 ) reported that the PI3K/mTOR dual inhibitor PKI-402 not only inhibits the proliferation of the cisplatin-sensitive ovarian cancer epithelial cell line A2780 but also inhibits the proliferation of the cisplatin-sensitive ovarian cancer epithelial cell line A2780. The cancer epithelial cell line SKOV3 has a significant inhibitory effect.…”

Section: Triazolopyrimidinesmentioning

confidence: 99%

Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment

Liang

et al. 2022

Front. Pharmacol.

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The PI3K-Akt-mTOR pathway is a viable target for cancer treatment and can be used to treat various malignant tumours, including follicular lymphoma and breast cancer. Both enzymes, PI3K and mTOR, are critical in this pathway. Hence, in recent years, an array of inhibitors targeting these two targets have been studied, showing dual PI3K/mTOR inhibition compared with single targeting small molecule inhibitors. Inhibitors not only inhibit cell proliferation but also promote cell apoptosis. These inhibitors show high potency and little drug resistance even at low doses, suggesting that PI3K/mTOR inhibitors are promising cancer drugs. Herein, we summarised the recent research of PI3K/mTOR dual inhibitors—for example, structure-activity relationship, pharmacokinetics, and clinical practice, and briefly commented on them.Clinical Trial Registration:https://clinicaltrials.gov.

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Dual PI3K/mTOR inhibitor PKI-402 suppresses the growth of ovarian cancer cells by degradation of Mcl-1 through autophagy

Cited by 31 publications

References 38 publications

PI3K/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic Neuroendocrine Tumors

PI3K/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic Neuroendocrine Tumors

The depletion of Circ‐PRKDC enhances autophagy and apoptosis in T‐cell acute lymphoblastic leukemia via microRNA‐653‐5p/Reelin mediation of the PI3K/AKT/mTOR signaling pathway

Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment

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