Resistance of colon cancer to 5-fluorouracil may be overcome by combination with chloroquine, an in vivo study

Sasaki, Kazuhito; Tsuno, Nelson H.; Sunami, Eiji; Kawai, Kazushige; Hongo, Kumiko; Hiyoshi, Masaya; Kaneko, Manabu; Murono, Koji; Tada, Noriko; Nirei, Takako; Takahashi, Koki; Kitayama, Joji

doi:10.1097/cad.0b013e328353f8c7

Cited by 56 publications

(40 citation statements)

References 34 publications

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“…S5B). These results support previous publications that suggest the potential of using endosome inhibitors in anticancer cocktails (36)(37)(38)(39) and provide a mechanism-driven treatment for patients carrying BRAFmutant colorectal tumors (Fig. 6).…”

Section: Endosomal Acidification Inhibitors Reduce the Growth And Metsupporting

confidence: 93%

BRAF-induced tumorigenesis is IKKα-dependent but NF-κB–independent

et al. 2015

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KRAS mutations contribute to cell proliferation and survival in numerous cancers, including colorectal cancers (CRC). One pathway through which mutant KRAS acts is an inflammatory pathway that involves the kinase IKK and activates the transcription factor NF-κB. BRAF, a kinase that is downstream of KRAS, is mutated in a subset of CRC and is predictive of poor prognosis and therapeutic resistance. We found that, in contrast to mutant KRAS, mutant BRAF (BRAF(V600E)) did not trigger NF-κB activation but instead triggered the phosphorylation of a proteolytic fragment of IKKα (p45-IKKα) in CRC cells. BRAF(V600E) CRC cells had a high abundance of phosphorylated p45-IKKα, which was decreased by a RAF inhibitor. However, the abundance and DNA binding of NF-κB in these cells were unaffected by the RAF inhibitor, and expression of BRAF(V600E) in human embryonic kidney-293T cells did not activate an NF-κB reporter. Moreover, BRAF-induced transformation of NIH-3T3 cells and BRAF-dependent transcription required phosphorylation of p45-IKKα. The kinase TAK1, which was associated with the endosomal compartment, phosphorylated p45-IKKα. Inhibition of endosomal vacuolar adenosine triphosphatase (V-ATPase) with chloroquine or bafilomycin A1 blocked p45-IKKα phosphorylation and induced apoptosis in BRAF-mutant CRC cells independent of autophagy. Treating mice with V-ATPase inhibitors reduced the growth and metastasis of BRAF(V600E) xenograft tumors in the cecum of mice.

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Section: Endosomal Acidification Inhibitors Reduce the Growth And Metsupporting

confidence: 93%

BRAF-induced tumorigenesis is IKKα-dependent but NF-κB–independent

et al. 2015

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“…CQ and HCQ are antimalarial drugs that recently attracted attention as potential anticancer agents and chemosensitizers, when used in combination with anticancer drugs (42)(43)(44)(45). In order to assess the efficacy of the combination of HCQ with conventional chemotherapeutics, three clinical trials (NCT00809237, NCT01649947, NCT00977470) are currently being launched.…”

Section: Autophagy Inhibition May Be a Promising Therapeutic Strategymentioning

confidence: 99%

Cotargeting EGFR and autophagy signaling: A novel therapeutic strategy for non-small-cell lung cancer

Sui

Kong

Zhu

et al. 2013

Molecular and Clinical Oncology

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Epidermal growth factor receptor (EGFR) somatic mutations are found in the majority of non-small-cell lung cancers (NSCLCs) and patients with NSCLC who harbor EGFR mutations have been shown to exhibit increased sensitivity to the small-molecule EGFR-tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. However, the majority of tumors develop acquired resistance to EGFR-TKIs after a median of 10-16 months, which limits the clinical efficacy of these drugs. Autophagy, an important homeostatic cellular recycling mechanism, has emerged as a potential target for the acquired resistance phenotype. Recently, several studies demonstrated that autophagy may be induced in a dose-dependent manner by treatment of multiple cancer cell lines with EGFR-TKIs . Furthermore, it was recently reported that autophagy, as a cytoprotective response, may be activated by EGFR-TKIs in lung cancer cells and that the inhibition of autophagy enhanced the cytotoxic effect of EGFR-TKIs. In this review, we aimed to focus on the association between resistance to EGFR-TKIs and autophagy, and assess whether autophagy inhibition represents a promising approach to improve the efficacy of EGFR-TKIs in the treatment of NSCLC patients.

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“…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%

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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Resistance of colon cancer to 5-fluorouracil may be overcome by combination with chloroquine, an in vivo study

Cited by 56 publications

References 34 publications

BRAF-induced tumorigenesis is IKKα-dependent but NF-κB–independent

BRAF-induced tumorigenesis is IKKα-dependent but NF-κB–independent

Cotargeting EGFR and autophagy signaling: A novel therapeutic strategy for non-small-cell lung cancer

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

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