Activation of PI3K/AKT/mTOR Pathway Causes Drug Resistance in Breast Cancer

Dong, Chao; Wu, Jiao; Chen, Yin; Nie, Jianyun; Chen, Ceshi

doi:10.3389/fphar.2021.628690

Cited by 186 publications

(156 citation statements)

References 133 publications

(156 reference statements)

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“…Activation of p38 and inhibition of PI3K/Akt/mTOR induced by these materials in cancer cells can induce pro-apoptotic changes, cell cycle arrest, the autophagic process, and downregulate cell migration, resulting in both cellular proliferation suppression and metastasis inhibition. Additionally, p38 inhibition and PI3K/Akt/mTOR activation in cancer cells frequently cause drug resistance [ 6 , 58 ]. This suggests that AR and its compounds that mediate these pathways in tumors can improve chemotherapy resistance.…”

Section: Discussionmentioning

confidence: 99%

Promising Anticancer Activities of Alismatis rhizome and Its Triterpenes via p38 and PI3K/Akt/mTOR Signaling Pathways

Jang

Lee

2021

Nutrients

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The flowering plant genus Alisma, which belongs to the family Alismataceae, comprises 11 species, including Alisma orientale, Alisma canaliculatum, and Alisma plantago-aquatica. Alismatis rhizome (Ze xie in Chinese, Takusha in Japanese, and Taeksa in Korean, AR), the tubers of medicinal plants from Alisma species, have long been used to treat inflammatory diseases, hyperlipidemia, diabetes, bacterial infection, edema, oliguria, diarrhea, and dizziness. Recent evidence has demonstrated that its extract showed pharmacological activities to effectively reverse cancer-related molecular targets. In particular, triterpenes naturally isolated from AR have been found to exhibit antitumor activity. This study aimed to describe the biological activities and plausible signaling cascades of AR and its main compounds in experimental models representing cancer-related physiology and pathology. Available in vitro and in vivo studies revealed that AR extract possesses anticancer activity against various cancer cells, and the efficacy might be attributed to the cytotoxic and antimetastatic effects of its alisol compounds, such as alisol A, alisol B, and alisol B 23-acetate. Several beneficial functions of triterpenoids found in AR might be due to p38 activation and inhibition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways. Moreover, AR and its triterpenes inhibit the proliferation of cancer cells that are resistant to chemotherapy. Thus, AR and its triterpenes may play potential roles in tumor attack, as well as a therapeutic remedy alone and in combination with other chemotherapeutic drugs.

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Section: Discussionmentioning

confidence: 99%

Promising Anticancer Activities of Alismatis rhizome and Its Triterpenes via p38 and PI3K/Akt/mTOR Signaling Pathways

Jang

Lee

2021

Nutrients

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“…AKT phosphorylation at Thr308 and Ser473 were detected in colon carcinomas and AKT activation may be important in the early inhibition of apoptosis during colon carcinogenesis [ 46 ]. In addition, previous studies suggested that PI3K/AKT promotes ABCG2 transcription mainly through Kelch-like ECH-associated protein 1 (KEAP1) and nuclear factor erythroid-derived (Nrf2) pathway which are downstream signals to AKT pathway that might also cause the ABCG2-mediated chemoresistance [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

VKNG-1 Antagonizes ABCG2-Mediated Multidrug Resistance via p-AKT and Bcl-2 Pathway in Colon Cancer: In Vitro and In Vivo Study

Narayanan

Fan

Gujarati

et al. 2021

Cancers

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The emergence of multidrug resistance (MDR) to chemotherapeutic drugs is a major problem in the therapy of cancer. Knowledge of the mechanisms of drug resistance in cancer is necessary for developing efficacious therapies. ATP-binding cassette (ABC) transporters are transmembrane proteins that efflux chemotherapeutic drugs from cancer cells, thereby producing MDR. Our research efforts have led to the discovery of VKNG-1, a compound that selectively inhibits the ABCG2 transporter and reverses resistanctabe to standard anticancer drugs both in vitro and in vivo. VKNG-1, at 6 µM, selectively inhibited ABCG2 transporter and sensitized ABCG2-overexpressing drug-resistant cancer cells to the ABCG2 substrate anticancer drugs mitoxantrone, SN-38, and doxorubicin in ABCG2-overexpressing colon cancers. VKNG- 1 reverses ABCG2-mediated MDR by blocking ABCG2 efflux activity and downregulating ABCG2 expression at the mRNA and protein levels. Moreover, VKNG-1 inhibits the level of phosphorylated protein kinase B (PKB/p-AKT), and B-cell lymphoma-2 (Bcl-2) protein which may overcome resistance to anticancer drugs. However, the in vitro translocation of ABCG2 protein did not occur in the presence of 6 µM of VKNG-1. In addition, VKNG-1 enhanced the anticancer efficacy of irinotecan in ABCG2- overexpressing mouse tumor xenografts. Overall, our results suggest that VKNG-1 may, in combination with certain anticancer drugs, represent a treatment to overcome ABCG2-mediated MDR colon cancers.

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“…MDA-MB-468 cells have been reported as cancer possessing overexpressed EGFR without mutation, but also with p53 mutation and PTEN deletion [32,33]. In the reported studies, it was shown that a synergistic effect with EGFR-TK inhibitor may occur in the case of using inhibitors of the PI3K/AKT/mTOR pathway because the PI3K/AKT/mTOR signaling pathway is hyper-activated by the deletion of PTEN [30,31]. Therefore, we evaluated their activity in the downstream signaling pathway of EGFR.…”

Section: Combinational Treatment Of Compounds 2b 2f and 2i With Gefitinibmentioning

confidence: 99%

“…In particular, a combination of the EGFR-TK inhibitor and different molecular targeted agents, such as the PI3K/AKT/mTOR or MEK inhibitors, were presented as one of strategy to overcome the resistance [27]. In contrast, EGFR mutations in TNBC are rare, but their resistance is conferred by PIK3CA mutation and activation of the PI3K/AKT/mTOR signaling pathway [28][29][30]. In a previous study, combinational treatment with inhibitors of the PI3K/AKT/mTOR pathway and the EGFR-TK inhibitor was used to increase the therapeutic effects of synergism against TNBC with resistance [30,31].…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, EGFR mutations in TNBC are rare, but their resistance is conferred by PIK3CA mutation and activation of the PI3K/AKT/mTOR signaling pathway [28][29][30]. In a previous study, combinational treatment with inhibitors of the PI3K/AKT/mTOR pathway and the EGFR-TK inhibitor was used to increase the therapeutic effects of synergism against TNBC with resistance [30,31]. Interestingly, MDA-MB-468 cells are basal cell carcinomas with p53 mutation and phosphatase and tensin homolog (PTEN) deletion as well as EGFR overexpression without EGFR mutation [32,33].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Biological Evaluation of (S)-2-(Substituted arylmethyl)-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide Analogs and Their Synergistic Effect against PTEN-Deficient MDA-MB-468 Cells

et al. 2021

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A series of twenty-six compounds of furfuryl or benzyl tetrahydropyrazino[1,2-a]indole analogs were synthesized and evaluated for cytotoxic activity against the estrogen receptor (ER)-positive breast cancer cell line (MCF-7) and the epidermal growth factor receptor (EGFR) over-expressed triple-negative breast cancer cell line (MDA-MB-468). Among them, compounds 2b, 2f and 2i showed more potent activity and selectivity against MDA-MB-468 cells than gefitinib, as an EGFR- tyrosine kinase inhibitor. In addition, it was confirmed by means of isobologram analysis of combinational treatment with gefitinib that they have a synergistic effect, especially compounds 2b and 2f, which inhibit Akt T308 phosphorylation. Moreover, it was confirmed that 2-benzyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide analogs (2b, 2f, and Ref2) tend to selectively inhibit PI3Kβ, which is involved in the phosphorylation of Akt.

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Activation of PI3K/AKT/mTOR Pathway Causes Drug Resistance in Breast Cancer

Cited by 186 publications

References 133 publications

Promising Anticancer Activities of Alismatis rhizome and Its Triterpenes via p38 and PI3K/Akt/mTOR Signaling Pathways

Promising Anticancer Activities of Alismatis rhizome and Its Triterpenes via p38 and PI3K/Akt/mTOR Signaling Pathways

VKNG-1 Antagonizes ABCG2-Mediated Multidrug Resistance via p-AKT and Bcl-2 Pathway in Colon Cancer: In Vitro and In Vivo Study

Synthesis and Biological Evaluation of (S)-2-(Substituted arylmethyl)-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide Analogs and Their Synergistic Effect against PTEN-Deficient MDA-MB-468 Cells

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