Augmentation of NVP-BEZ235's anticancer activity against human lung cancer cells by blockage of autophagy

Xu, Cheng-Xiong; Zhao, Li‐Xia; Yue, Ping; Fang, Guofu; Tao, Hui; Owonikoko, Taofeek K.; Ramalingam, Suresh S.; Khuri, Fadlo R.; Sun, Shi‐Yong

doi:10.4161/cbt.12.6.16397

Cited by 55 publications

(53 citation statements)

References 26 publications

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“…Conversely, only quite modest improvement in response to chemotherapeutic agents was detected for chloroquine in combination with an mTOR inhibitor in MCF-7 xenografts (Loehberg et al, 2012), with voranistat in colon carcinoma (Carew et al, 2010), with perifosine in lung cancer xenografts (Fu et al, 2009), with a dual phosphatidylinositide 3-kinase/ protein kinase B/mTOR inhibitor in non-small cell lung cancer xenografts (Xu et al, 2011), with a retinoic acid metabolism blocker in breast tumor cells (Godbole et al, 2012), and with panobinostat in breast cancer (Rao et al, 2012); in the latter studies, the lack of impact could be ascribed to the use of an unusually low dose of chloroquine of 10 mg/kg, which was apparently necessitated by the high degree of toxicity that was observed with chloroquine alone in this work.…”

Section: Discussionmentioning

confidence: 99%

“…as indicated: (a) 25 mg/kg CQ (chloroquine), (b) 50 mg/kg CQ, (c) 100 mg/kg CQ, or (d) phosphate-buffered saline. The CQ doses chosen were based on the available literature, where studies have generally been performed using CQ at 50-60 mg/kg (Fu et al, 2009;Carew et al, 2010;Jiang et al, 2010;Wu et al, 2010;Ding et al, 2011;Lopez et al, 2011;Mirzoeva et al, 2011;Pan et al, 2011;Shi et al, 2011;Xu et al, 2011;Ghadimi et al, 2012;Godbole et al, 2012;Guo et al, 2012;Hu et al, 2012;Liang et al, 2012;Loehberg et al, 2012;Rao et al, 2012;Sasaki et al, 2012). Additional experiments were conducted where the mice were exposed to g-irradiation using a 137 Cs irradiator as indicated: (e) 5 Gy IR (ionizing radiation), (f) 10 Gy IR, (g) 15 Gy IR, (h) 10Gy IR 1 14 days CQ i.p.…”

Section: Methodsmentioning

confidence: 99%

“…An extensive number of studies in cell culture (for example, among many others, Paglin et al, 2001;Kanzawa et al, 2004;Boya et al, 2005;Zhao et al, 2005;Amaravadi et al, 2007;Apel et al, 2008;Qadir et al, 2008;Livesey et al, 2009;Solomon and Lee, 2009;Ma et al, 2011;Wilson et al, 2011;Bristol et al, 2012), as well as a limited number of studies in animal models (Fu et al, 2009;Carew et al, 2010;Jiang et al, 2010;Wu et al, 2010;Ding et al, 2011;Lopez et al, 2011;Mirzoeva et al, 2011;Pan et al, 2011;Shi et al, 2011;Xu et al, 2011;Ghadimi et al, 2012;Godbole et al, 2012;Guo et al, 2012;Hu et al, 2012;Liang et al, 2012;Loehberg et al, 2012;Rao et al, 2012;Sasaki et al, 2012), have been performed combining chloroquine or hydroxychloroquine with chemotherapeutic drugs or radiation. Furthermore, a number of clinical trials have been initiated to test this premise in patients (Sotelo et al, 2006;Solomon and Lee, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Autophagy Inhibition for Chemosensitization and Radiosensitization in Cancer: Do the Preclinical Data Support This Therapeutic Strategy?

Bristol

Emery

Maycotte

et al. 2013

J Pharmacol Exp Ther

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Recognition of the cytoprotective functions of autophagy that occur in tumor cells exposed to various forms of chemotherapy or radiation has generated intense interest in the possibility that pharmacological interference with autophagy could provide a clinical strategy for overcoming therapeutic resistance. Multiple clinical trials are currently in progress to evaluate the antimalarial agent chloroquine (generally in its clinical formulation as hydroxychloroquine) and its impact on various forms of cancer therapy. In this commentary/review, we focus on the relatively limited number of studies in the literature where chloroquine has been tested in combination with chemotherapy or radiation in experimental tumor-bearing animal models. We also present recent data from our own laboratories, in cell culture experiments as well as in vivo studies, which demonstrate that neither chloroquine nor silencing of an autophagy regulatory gene was effective in conferring radiation sensitivity in an experimental model of breast cancer. The capacity for sensitization by chloroquine appears to be quite wide-ranging, with dramatic effects for some drugs/tumor models and modest or minimal effects in others. One possible caveat is that, with only a few exceptions, experiments have generally been performed in xenograft models, thereby eliminating the involvement of the immune system, which might ultimately be proven to play a central role in determining the effectiveness of autophagy inhibition in chemosensitization or radiosensitization. Nevertheless, a careful review of the current literature suggests that caution is likely to be warranted in translating preclinical findings relating to autophagy inhibition as an adjunctive therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Autophagy Inhibition for Chemosensitization and Radiosensitization in Cancer: Do the Preclinical Data Support This Therapeutic Strategy?

Bristol

Emery

Maycotte

et al. 2013

J Pharmacol Exp Ther

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“…The combination of BEZ235, the dual PI3K/mTOR inhibitor, with temsirolimus resulted in cell death due to autophagy (Yang et al, 2011). Inhibition of autophagy has also enhanced the effect of PI3K/mTOR inhibition in neurological tumours (Ghadimi et al, 2012) and lung cancer (Xu et al, 2011).…”

Section: Tablementioning

confidence: 99%

Increased drug resistance is associated with reduced glucose levels and an enhanced glycolysis phenotype

Bhattacharya

Low

Soh

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSEThe testing of anticancer compounds in vitro is usually performed in hyperglycaemic cell cultures, although many tumours and their in vivo microenvironments are hypoglycaemic. Here, we have assessed, in cultures of tumour cells, the effects of reduced glucose levels on resistance to anticancer drugs and investigated the underlying cellular mechanisms. EXPERIMENTAL APPROACHPIK3CA mutant (AGS, HGC27), and wild-type (MKN45, NUGC4) gastric cancer cells were cultured in high-glucose (HG, 25 mM) or low-glucose (LG, 5 mM) media and tested for sensitivity to two cytotoxic compounds, 5-fluorouracil (5-FU) and carboplatin, the PI3K/mTOR inhibitor, PI103 and the mTOR inhibitor, Ku-0063794. KEY RESULTSAll cells had increased resistance to 5-FU and carboplatin when cultured in LG compared with HG conditions despite having similar growth and cell cycle characteristics. On treatment with PI103 or Ku-0063794, only the PIK3CA mutant cells displayed increased resistance in LG conditions. The PIK3CA mutant LG cells had selectively increased p-mTOR, p-S6, p-4EBP1, GLUT1 and lactate production, and reduced reactive oxygen species, consistent with increased glycolysis. Combination analysis indicated PI103 and Ku-0063794 were synergistic in PIK3CA mutant LG cells only. Synergism was accompanied by reduced mTOR signalling and increased autophagy. CONCLUSIONS AND IMPLICATIONSHypoglycaemia increased resistance to cytotoxic agents, especially in tumour cells with a high dependence on glycolysis. Dual inhibition of the PI3K/mTOR pathway may be able to attenuate such hypoglycaemia-associated resistance. Abbreviations

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“…A549/YFP-LC3 stable lines were provided by Dr. ShiYong Sun (Emory University) [33]. These cell lineswere all maintained in RPMI 1640 medium supplemented with 10% fetal bovine serum at 37 °C in a humidified atmosphere containing 5% CO 2 .…”

Section: Cell Lines and Cell Culturementioning

confidence: 99%

Blockade Efficacy of MEK/ERK-Dependent Autophagy Enhances PI3K/Akt Inhibitor NVP-BKM120's Therapeutic Effectiveness in Lung Cancer Cells

Ren

Chen

2016

Chest

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Augmentation of NVP-BEZ235's anticancer activity against human lung cancer cells by blockage of autophagy

Cited by 55 publications

References 26 publications

Autophagy Inhibition for Chemosensitization and Radiosensitization in Cancer: Do the Preclinical Data Support This Therapeutic Strategy?

Autophagy Inhibition for Chemosensitization and Radiosensitization in Cancer: Do the Preclinical Data Support This Therapeutic Strategy?

Increased drug resistance is associated with reduced glucose levels and an enhanced glycolysis phenotype

Blockade Efficacy of MEK/ERK-Dependent Autophagy Enhances PI3K/Akt Inhibitor NVP-BKM120's Therapeutic Effectiveness in Lung Cancer Cells

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