Oncology Letters
·
2020
·Vol. 20
·期 6
·1-1
·
IF 2.311
Hao Zhu,Yuhuan Shi,Xiuxiu Jiao,Gang Yang,Rong Wang,Yongfang Yuan
Cisplatin resistance is an obstacle for the effective treatment of non‑small cell lung cancer (NSCLC). The combined use of two or more chemotherapeutic agents displays advantages for the clinical treatment of drug‑resistant lung cancer. The present study aimed to assess the synergy of the dual PI3K/Akt/mTOR signaling pathway inhibitor NVP‑BEZ235 and cisplatin, a chemotherapeutic agent, on proliferation, apoptosis, cell cycle arrest and protein expression in cisplatin‑resistant NSCLC A549/diamminedichloroplatinum resistance (DDP) cells. Cell proliferation was determined by performing Cell Counting Kit 8 and colony formation assays. Combination index (CI) was used to assess the combinatorial effects of NVP‑BEZ235 and cisplatin. Cellular apoptosis and cell cycle arrest were detected via flow cytometry. Western blotting was performed to evaluate protein expression levels relative to β‑actin. Cisplatin and NVP‑BEZ235 displayed the strongest synergy (CI50=0.23) at the mass ratio of 10:1. The half inhibitory concentrations of cisplatin and NVP‑BEZ235 at 10:1 were 1.53 and 0.15 µg/ml, respectively. Compared with the control group, the combination of cisplatin and NVP‑BEZ235 induced cell apoptosis and inhibited colony formation. Furthermore, compared with the control group, phosphorylation of Akt and p70S6 Kinase was significantly inhibited and cell cycle was arrested at G0G1 phase in the combination treatment group. The expression levels of drug efflux proteins, such as multidrug resistance‑associated protein 1 and ATP‑binding cassette sub‑family G member 2, were significantly decreased when A549/DDP cells were treated with a combination of cisplatin and NVP‑BEZ235 compared with the control group. Collectively, the present study indicated that the combined treatment of cisplatin and NVP‑BEZ235 displayed synergistic antitumor effects on drug‑resistant A549/DDP cells, by which the antiproliferative effects may occur via inhibition of the PI3K/Akt/mTOR signaling pathway and downregulation of drug efflux.
研究领域:
肿瘤学
·
药理学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2026
·
IF 5.9
Chen Guo,Yunqing Xie,Ziyao Lu,Shanshan Chen,Lili Su,Xiaowei Lin,Li Chen,Shaukat Semm Ally Basinda,Yang Sun,Jianyong Liu,Qinying Liu
Hypoxia is a distinctive characteristic of solid tumors, limiting the efficiency of photodynamic therapy (PDT). In this study, transcriptomics was applied to analyze the changes in mRNA levels in mouse tumors treated with multiple photodynamic therapy sessions, revealing that 12 genes in the PI3K/mTOR pathway were significantly upregulated. In order to improve delivery efficiency and enhance the efficacy of PDT photosensitizers, a nitroreductase-responsive BODIPY prodrug (BNP) was designed and employed to encapsulate a PI3K/ mTOR dual inhibitor (BEZ235) to self-assemble into nanoparticles (BNP@BEZ NPs). The fluorescence level of BNP@BEZ NPs in hypoxic cells was 12.20-fold that in normoxic cells because of the responsiveness of nitrobenzyl groups to hypoxia. Such minimized off-target effects also resulted in preferential intratumoral activation of prodrugs. Meanwhile, BEZ co-loading alleviated tumor hypoxia and increased intracellular ROS levels to 155.26% compared to blank prodrug nanoparticles. BNP@BEZ NPs-mediated PI3K/mTOR inhibition and apoptosis of tumor cells exhibited sufficient antitumor efficacy with a tumor inhibition rate of 93.31%. In conclusion, this study confirms that the PI3K/mTOR pathway promotes tumor PDT resistance by enhancing mitochondrial respiration. The hypoxic -responsive photodynamic properties of BNP, combined with BEZ's oxygen consumption-inhibiting capacity, can enhance tumor suppression rates. This strategy of nanomedicine development by capitalizing on the synergistic effect between active ingredients will avoid the low efficacy and adverse effects of monotherapies.
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DOI
PubMed
高影响因子
ANTI-CANCER DRUGS
·
2019
·Vol. 30
·期 1
·46-55
·
IF 1.801
Lin Fuxing,Yang Jie,Muhammad Umair,Sun Jing,Huang Zhenghua,Li Wei,Lv Fengxia,Lu Zhaoxin
Bacillomycin D can inhibit the growth of Aspergillus ochraceus in food samples. In addition, it can induce apoptosis in and inhibit the proliferation of cancer cells, although the details of this mechanism are unknown. In this study, we separated bacillomycin D-C14, D-C15, D-C16
monomers from the Bacillus subtilis strain fmbJ. The bacillomycin D monomers containing longer fatty acid chains better induced apoptosis in Bgc-823, Sgc-7901, and Hgc-27 gastric cancer cells. The Bgc-823 cell line was the most sensitive. Acridine orange-ethidium bromide staining indicated
that bacillomycin D-C16-induced Bgc-823 cell death by triggering apoptosis, characterized by membrane blebbing, cellular shrinkage, and DNA fragmentation. Flow cytometric analysis showed a bacillomycin D-C16 dose-dependent trigger of Bgc-823 apoptosis. Bacillomycin D-C16-induced the mitochondrial
pathway, as indicated by a reduced Bcl-2/Bax expression ratio, enhanced cytochrome C release, and higher levels of cleaved caspase-3. Furthermore, bacillomycin D-C16 effectively repressed phosphorylation of the serine–threonine protein kinase Akt at Ser-473 and increased the levels of
the FoxO3a protein. The combination of the PI3K/Akt-inhibitor BEZ235 with bacillomycin D-C16 enhanced the apoptosis of Bgc-823 cells. Together, these findings indicated that bacillomycin D-C16 induces apoptosis through the PI3K/Akt and FoxO3a signaling pathways.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2024
·
IF 9.4
Jianan Qiao,Shuhui Liu,Yanfeng Huang,Xiang Zhu,Chenyang Xue,Yan Wang,Hui Xiong,Jing Yao
Clinical pancreatic ductal adenocarcinoma (PDAC) treatment is severely limited by lack of effective KRAS suppression strategies. To address this dilemma, a reactive oxygen species (ROS)-responsive and PDAC-targeted nanodrug named Z/B-PLS was constructed to confront KRAS through dual-blockade of its downstream PI3K/AKT/mTOR and RAF/MEK/ERK for enhanced PDAC treatment. Specifically, photosensitizer zinc phthalocyanine (ZnPc) and PI3K/mTOR inhibitor BEZ235 (BEZ) were co-loaded into PLS which was constructed by click chemistry conjugating MEK inhibitor selumetinib (SEL) to low molecular weight heparin with ROS-responsive oxalate bond. The BEZ and SEL blocked PI3K/AKT/mTOR and RAF/MEK/ERK respectively to remodel glycolysis and non-canonical glutamine metabolism. ZnPc mediated photodynamic therapy (PDT) could enhance drug release through ROS generation, further facilitating KRAS downstream dual-blockade to create treatment-promoting drug delivery-therapeutic positive feedback. Benefiting from this broad metabolic modulation cascade, the metabolic symbiosis between normoxic and hypoxic tumor cells was also cut off simultaneously and effective tumor vascular normalization effects could be achieved. As a result, PDT was dramatically promoted through glycolysis-non-canonical glutamine dual-metabolism regulation, achieving complete elimination of tumors in vivo . Above all, this study achieved effective multidimensional metabolic modulation based on integrated smart nanodrug delivery, helping overcome the therapeutic challenges posed by KRAS mutations of PDAC.
研究领域:
肿瘤学
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药理学
·
纳米技术
·
代谢调控
·
光疗
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产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2023
·Vol. 14
·期 10
·1-17
·
IF 9
Deng Huan,Chen Yamei,Wang Li,Zhang Yibi,Hang Qingqing,Li Peijing,Zhang Peng,Ji Jing,Song Hai,Chen Ming,Jin Ying
Our previous study revealed that PI3K/AKT/mTOR signaling was associated with SCLC radioresistance. SBC2 cells were used as primary radioresistance models, while H446 cells were continuously exposed to ionizing radiation (IR) to develop acquired radioresistance. Cell viability and apoptosis assays were used to investigate synergistic effects of BEZ235/GSK2126458 and IR in vitro, while immunoblotting, metabolite quantitative analysis and bioinformatic analyses were utilized to explore the underlying mechanism. Both genetically engineered mouse models (GEMM) and subcutaneous tumor models were used to confirm the synergistic effect in vivo. Key molecules of PI3K/AKT/mTOR signaling were upregulated after IR, which was correlated with primary radioresistance, and they were more expressed in acquired radioresistant cells. BEZ235/GSK2126458 effectively enhanced the cytotoxic effects of IR. BEZ235/GSK2126458 plus IR elevated γ-H2AX and p-Nrf2 expression, suggesting DNA and oxidative stress damage were intensified. Mechanistically, BEZ235/GSK2126458 plus IR significantly reduced the expression of G6PD protein, the rate-limiting enzyme of the pentose phosphate pathway (PPP). In detail, PI3K/mTOR inhibitors reinforced interaction between G6PD and HSPA8/HSC70, and G6PD was degraded by chaperone-mediated autophagy processes. Their metabolites (NADPH and R-5P) were decreased, and ROS levels were indirectly elevated, both of which exacerbated cell death. PI3K/AKT/mTOR signaling activator, insulin, enhanced SCLC radioresistance, while the synergistic effect of BEZ235/GSK2126458 and IR can be attenuated by N-acetylcysteine, and enhanced by 6-amino niacinamide. GEMM and allograft transplantation assays further confirmed their synergistic effect in vivo. This study provided insights into the connection between PI3K/AKT/mTOR signaling and the PPP underlying radioresistance and provided evidence of mechanisms supporting PI3K/mTOR inhibitors as possible therapeutic strategies to abrogate SCLC radioresistance.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
分子生物学
·
放射生物学
✓ 已验证
DOI
PubMed
高影响因子
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