The dual PI3K/mTOR inhibitor NVP-BEZ235 enhances nab-paclitaxel antitumor response in experimental gastric cancer

Zhang, Chang Hua; Awasthi, Niranjan; Schwarz, Margaret A.; Schwarz, Roderich E.

doi:10.3892/ijo.2013.2099

Cited by 28 publications

(23 citation statements)

References 43 publications

(45 reference statements)

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“…Furthermore, our results showed that the miR-21 modulated the expression of P-gp, which is considered to contribute to the development of drug The primary anti-tumor effect of PTX is mediated by microtubule stabilization, although other mechanisms have also been reported to mediate paclitaxel-induced cell death such as induction of mitochondrion stress through the activation of p38 [26]. In the context of PTX-resistance, a verity of molecules and signaling pathways has been reported to be associated with the sensitivity of gastric cancer cells to PTX, such as Class III beta-tubulin (TUBB3) [27], PI3K/AKT/mTOR signaling [28], NF-jB signaling [29], SRC [30], FGFR2 [31], VEGFR2 [32], HBEGF [33] and CHK2 [34]. In addition to findings, previous studies also reported the role of miRNAs in modulating sensitivities of gastric cancer cells to PTX, including miR-27 [35], miR23a [36] and miR-34c-5p [37].…”

Section: Discussionmentioning

confidence: 98%

Antagonism of miRNA-21 Sensitizes Human Gastric Cancer Cells to Paclitaxel

Jin

Liu

Wang

2015

Cell Biochem Biophys

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The development of drug resistance has largely limited the clinical outcome of anti-cancer treatment. Recent work has highlighted the involvement of non-coding RNAs, microRNAs (miRNAs), in cancer development. The present study aimed to investigate the role of miR-21 in the development of drug resistance to paclitaxel in gastric cancer cells. Our study found that the expression of miR-21 upregulated in the paclitaxel resistant cell line SGC7901/paclitaxel compared to its parental line SGC7901. Moreover, over-expression of miR-21 significantly decreased antiproliferative effects and apoptosis induced by paclitaxel, while knockdown of miR-21 dramatically increased antiproliferative effects and apoptosis induction by paclitaxel. Moreover, our results demonstrated that miR-21 may modulate the sensitivity to PTX, at least in part, by regulating the expression of P-glycoprotein.

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Section: Discussionmentioning

confidence: 98%

Antagonism of miRNA-21 Sensitizes Human Gastric Cancer Cells to Paclitaxel

Jin

Liu

Wang

2015

Cell Biochem Biophys

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“…Mitochondrial permeability transition is regulated by a variety of factors, including reactive oxygen [52]. PTX could induce mitochondrial damage, especially in mitochondrial membranes [53]. Recent studies also show that selenized compound could induce apoptosis of A-375 cells by activating the mitochondrial pathway [54].…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanism for Selective Cytotoxicity towards Cancer Cells of Diselenide-Containing Paclitaxel Nanoparticles

Zhang

et al. 2019

Int. J. Biol. Sci.

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Diselenide-containing paclitaxel nanoparticles (SePTX NPs) indicated selectivity of cytotoxicity between cancerous and normal cells in our previous work. Herein, the mechanism is revealed by molecular biology in detail. Cancer cells and normal cells were treated with the SePTX NPs and cell proliferation was measured using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay and cell morphology. Measurement of reactive oxygen species (ROS) levels and biochemical parameters were employed to monitor oxidative stress of the cells. JC-1 assay was used to detect the mitochondrial dysfunction of the cells. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) analysis was used to detect apoptosis of the cells. Immunofluorescence analysis and western blotting were employed to monitor changes in signaling pathway-related proteins. Compared with PTX, SePTX NPs has a good selectivity to cancer cells and can obviously induce the proliferation damage of cancer cells, but has no significant toxicity to normal cells, indicating that SePTX NPs has a specific killing effect on cancer cells. The results of mechanism research show that SePTX NPs can successfully inhibit the depolymerization of microtubules and induce cell cycle arrest, which is related to the upregulation of p53 and CyclinB1. Simultaneously, SePTX NPs can successfully induce oxidative stress, cause mitochondrial dysfunction, resulting in mitochondrial pathway-mediated apoptosis, which is related to the upregulation of autophagy-related protein LC3-II. On the other hand, lewis lung cancer C57BL/6 mice were used to evaluate the anti-tumor effects of SePTX NPs in vivo. Our data show that SePTX NPs exhibited high inhibiting efficiency against the growth of tumors and were able to reduce the side effects. Collectively, these data indicate that the high antitumor effect and selective cytotoxicities of SePTX NPs is promising in future cancer therapy.

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“…Indeed, limited information on the combinational therapy of BEZ235 and PTX in ovarian, 31 gastric, 7 pancreatic, 32 and thyroid 33 cancers suggests a synergistic inhibitory effect on cancer cell growth through an induced apoptosis. However, this combination therapy has not been documented in colon cancer.…”

Section: Introductionmentioning

confidence: 99%

“…[6][7][8] Lipid nanocapsule-loaded PTX was also shown to be more effective for oral administration with enhanced bioavailability.…”

Section: Introductionmentioning

confidence: 99%

“…19,28 It has been shown that PTX can induce a synergistic effect with a few other drugs on a few different cancers. 7,31 We believed that it would have a similar effect on colon cancer. Chen et al 39,40 have shown that the activation of the PI3K/Akt pathway can reduce the effect of chemotherapeutic agents in colon cancer cell lines, and inhibition of this pathway can increase the sensitivity of HT-29 cells to 5-FU.…”

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confidence: 99%

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Synergistic inhibition of colon cancer cell growth with nanoemulsion-loaded paclitaxel and PI3K/mTOR dual inhibitor BEZ235 through apoptosis

Zou¹,

Li²,

Carcedo³

et al. 2016

IJN

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Colon cancer is the third most common cancer in the world, with drug resistance and metastasis being the major challenges to effective treatments. To overcome this, combination therapy with different chemotherapeutics is a common practice. In this study, we demonstrated that paclitaxel (PTX) together with BEZ235 exhibited a synergetic inhibition effect on colon cancer cell growth. Furthermore, nanoemulsion (NE)-loaded PTX and BEZ235 were more effective than the free drug, and a combination treatment of both NE drugs increased the efficiency of the treatments. BEZ235 pretreatment before adding PTX sensitized the cancer cells further, suggesting a synergistic inhibition effect through the phosphatidylinositol-3-kinases/protein kinase B/mammalian target of rapamycin pathway. The 50% inhibitory concentrations for BEZ235 were 127.1 nM and 145.0 nM and for PTX 9.7 nM and 9.5 nM for HCT-116 and HT-29 cells, respectively. When loaded with NE the 50% inhibitory concentrations for BEZ235 decreased to 52.6 nM and 55.6 nM and for PTX to 1.9 nM and 2.3 nM for HCT-116 and HT-29 cells, respectively. Combination treatment with 10 nM NE-BEZ235 and 0.6 nM and 1.78 nM NE-PTX could kill 50% of HCT-116 and HT-29, respectively. The cell death caused by the treatment was through apoptotic cell death, which coincided with decreased expression of anti-apoptotic protein B-cell lymphoma 2. Our data indicate that the combination therapy of PTX with the phosphatidylinositol-3-kinases/protein kinase B/mammalian target of rapamycin dual inhibitor BEZ235 using NE delivery may hold promise for a more effective approach for colon cancer treatment.

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The dual PI3K/mTOR inhibitor NVP-BEZ235 enhances nab-paclitaxel antitumor response in experimental gastric cancer

Cited by 28 publications

References 43 publications

Antagonism of miRNA-21 Sensitizes Human Gastric Cancer Cells to Paclitaxel

Antagonism of miRNA-21 Sensitizes Human Gastric Cancer Cells to Paclitaxel

Molecular Mechanism for Selective Cytotoxicity towards Cancer Cells of Diselenide-Containing Paclitaxel Nanoparticles

Synergistic inhibition of colon cancer cell growth with nanoemulsion-loaded paclitaxel and PI3K/mTOR dual inhibitor BEZ235 through apoptosis

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