Akt and p53 are potential mediators of reduced mammary tumor growth by Chloroquine and the mTOR inhibitor RAD001

Loehberg, Christian R.; Strissel, Pamela L.; Dittrich, Ralf; Strick, Reiner; Dittmer, J; Dittmer, Angela; Fabry, Ben; Kalender, Willi A.; Koch, Thorsten; Wachter, David; Groh, N; Polier, A; Brandt, Ina; Lotz, Laura; Hoffmann, Inge; Koppitz, Florentine; Oeser, Sonja; Mueller, Andreas; Fasching, Peter A.; Lux, Michael P.; Beckmann, Matthias W.; Schrauder, Michael G.

doi:10.1016/j.bcp.2011.11.022

Cited by 43 publications

(38 citation statements)

References 53 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: 97%

“…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: 97%

Section: Methodsmentioning

confidence: 99%

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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“…40 Furthermore, a p53 activator (chloroquine) in combination with RAD001 reduced mammary tumors in a mouse model. 41 Finally, consistent with rapamycin's ability to block bladder cancer development, deletion of p53 and PTEN led to invasive bladder cancer with upregulated mTOR. 42 These data support the possibility that p53 is important for rapamycin-mediated tumor activity.…”

Section: P53 Inhibits Mtorc1 To Suppressmentioning

confidence: 93%

mTORC1 and p53

et al. 2012

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“…These results suggest that CN-A as well as 17-AAG or ATO is possibly a suitable candidate for combination therapy with Rapa to inhibit solid tumor cells. Recently, Loehberg el al (34) reported that anti-malarial chloroquine could prevent rapalog RAD001-induced Akt activation and enhance RAD001-induced inhibition of cell proliferation in luminal MCF-7 cells. However, this combined treatment was not effective in mesenchymal MDA-MB231 breast cancer cells (34).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of rapamycin-induced Akt phosphorylation by cotylenin A correlates with their synergistic growth inhibition of cancer cells

Kasukabe

Okabe‐Kado

Haranosono

et al. 2012

International Journal of Oncology

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Abstract. Cotylenin A, a plant growth regulator, and rapamycin, an inhibitor of the mammalian target of rapamycin, are potent inducers of differentiation in myeloid leukemia cells and also synergistically inhibit the proliferation of several human breast cancer cell lines including MCF-7 in vitro and in vivo. However, the mechanisms of the combined effects of cotylenin A and rapamycin are still unknown. Activated Akt induced by rapamycin has been suggested to attenuate the growth-inhibitory effects of rapamycin, serving as a negative feedback mechanism. In this study, we found that cotylenin A could suppress rapamycin-induced phosphorylation of Akt (Ser473) in MCF-7 cells and lung carcinoma A549 cells and that cotylenin A also enhanced the rapamycin-induced growth inhibition of MCF-7 and A549 cells. ISIR-005 (a synthetic cotylenin A-derivative) was able to enhance rapamycin-induced growth inhibition and could also markedly inhibit rapamycininduced phosphorylation of Akt. We also found that the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) or arsenic trioxide (ATO) in combination with rapamycin markedly inhibited the growth of MCF-7 cells and 17-AAG or ATO suppressed rapamycin-induced phosphorylation of Akt. The PI3K inhibitor LY294002 also suppressed rapamycin-induced phosphorylation of Akt and combined treatment showed synergistic growth inhibition of MCF-7 cells. Rapamycin inhibited growth more significantly in Akt siRNA-transfected MCF-7 cells than in control siRNA-transfected MCF-7 cells. These results suggest that the inhibition of rapamycin-induced Akt phosphorylation by cotylenin A correlates with their effective growth inhibition of cancer cells.

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Akt and p53 are potential mediators of reduced mammary tumor growth by Chloroquine and the mTOR inhibitor RAD001

Cited by 43 publications

References 53 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?

mTORC1 and p53

Inhibition of rapamycin-induced Akt phosphorylation by cotylenin A correlates with their synergistic growth inhibition of cancer cells

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