Hydroxychloroquine potentiates the anti-cancer effect of bevacizumab on glioblastoma via the inhibition of autophagy

Liu, Linqing; Wang, Shibing; Shao, Yanfei; Shi, Jiana; Wang, Wei; Chen, Wan-yuan; Ye, Ziqi; Jiang, Jialiang; Fang, Qingxia; Zhang, Guobing; Xuan, Zixue

doi:10.1016/j.biopha.2019.109339

Cited by 35 publications

(20 citation statements)

References 19 publications

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“…According to our previous studies[ 18 , 20 ], HCQ could inhibit tumor autophagy. To confirm the effect of curcumin-induced autophagy on curcumin-mediated cell inhibition of LGR5(+) colorectal CSCs, cells were co-treated and incubated with curcumin (5 μM) and HCQ (10 μM); sphere formation and cell viability were then analyzed.…”

Section: Colorectal Cscsmentioning

confidence: 99%

“…Because the green fluorescent protein (GFP) signals can be quenched and the monomeric red fluorescent protein (mRFP) signal is more stable in the acidic environment of the lysosome, autolysosomes, and autophagosomes were labeled with mRFP (red) or GFP (green), respectively[ 18 ]. The LGR5(+) colorectal CSCs were transfected with Ad-mCherry-GFP-LC3B (2.51 × 10 10 PFU/mL), and treated with different concentrations of curcumin (1 μM and 5 μM) or rapamycin (100 nM) for 48 h. In this study, autophagy inducer rapamycin served as a positive control group.…”

Section: Colorectal Cscsmentioning

confidence: 99%

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Curcumin suppresses LGR5(+) colorectal cancer stem cells by inducing autophagy and via repressing TFAP2A-mediated ECM pathway

et al. 2021

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Colorectal cancer stem cells (CSCs) have the potential for self-renewal, proliferation, and differentiation. And LGR5 is a stem cell marker gene of colorectal cancer. Curcumin can suppress oncogenicity of many cancer cells, yet the effect and mechanism of curcumin in LGR5(+) colorectal cancer stem cells (CSCs) have not been studied. In this study, we studied the effect of curcumin on LGR5(+) colorectal CSCs using the experiments of tumorsphere formation, cell viability and cell apoptosis. Then autophagy analysis, RNA-Seq, and real-time PCR were used to identify the mechanism responsible for the inhibition of LGR5(+) colorectal CSCs. Our results showed that curcumin inhibited tumorsphere formation, decreased cell viability in a dose-dependent manner, and also promoted apoptosis of LGR5(+) colorectal CSCs. Next, we found curcumin induced autophagy of LGR5(+) colorectal CSCs. When LGR5(+) colorectal CSCs were co-treated with curcumin and the autophagy inhibitor (hydroxychloroquine), curcumin-induced cell proliferation inhibition decreased. In addition, we also found that curcumin inhibited the extracellular matrix (ECM)-receptor interaction pathway via the downregulation of the following genes: GP1BB, COL9A3, COMP, AGRN, ITGB4, LAMA5, COL2A1, ITGB6, ITGA1, and TNC. Further, these genes were transcriptionally regulated by TFAP2A, and the high expression of TFAP2A was associated with poor prognosis in colorectal cancer. In conclusion, curcumin suppressed LGR5(+) colorectal CSCs, potentially by inducing autophagy and repressing the oncogenic TFAP2A-mediated ECM pathway. Graphic abstract

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Section: Colorectal Cscsmentioning

confidence: 99%

Section: Colorectal Cscsmentioning

confidence: 99%

Curcumin suppresses LGR5(+) colorectal cancer stem cells by inducing autophagy and via repressing TFAP2A-mediated ECM pathway

et al. 2021

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“…Bevacizumab is a monoclonal antibody that binds to and inhibits the cellular activity of the vascular endothelial growth factor (VEGF), a potent angiogenic factor that stimulates the formation of blood vessels. The role of autophagy in resistance to bevacizumab has been demonstrated in several cancers, including gliomas, colorectal cancers, and liver cancers [113,192,193,194,195,196]. Most recently, it has been demonstrated that treatment of glioblastomas with bevacizumab induces autophagy, and the pharmacological inhibition of autophagy, using HCQ, in combination with bevacizumab resulted in a greater mitigation of cancer cell growth compared to either treatment alone [194].…”

Section: Autophagy Contributes To Treatment Resistance In Cancermentioning

confidence: 99%

“…The role of autophagy in resistance to bevacizumab has been demonstrated in several cancers, including gliomas, colorectal cancers, and liver cancers [113,192,193,194,195,196]. Most recently, it has been demonstrated that treatment of glioblastomas with bevacizumab induces autophagy, and the pharmacological inhibition of autophagy, using HCQ, in combination with bevacizumab resulted in a greater mitigation of cancer cell growth compared to either treatment alone [194]. Similarly, bevacizumab treatment was also associated with an upregulation of autophagy in colorectal cancer cells, and the pharmacological or genetic inhibition of autophagy both improved the growth inhibitory and pro-apoptotic effects of bevacizumab in vitro and in vivo [192].…”

Section: Autophagy Contributes To Treatment Resistance In Cancermentioning

confidence: 99%

Molecular Mechanisms Underlying Autophagy-Mediated Treatment Resistance in Cancer

Gorski

2019

Cancers

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Despite advances in diagnostic tools and therapeutic options, treatment resistance remains a challenge for many cancer patients. Recent studies have found evidence that autophagy, a cellular pathway that delivers cytoplasmic components to lysosomes for degradation and recycling, contributes to treatment resistance in different cancer types. A role for autophagy in resistance to chemotherapies and targeted therapies has been described based largely on associations with various signaling pathways, including MAPK and PI3K/AKT signaling. However, our current understanding of the molecular mechanisms underlying the role of autophagy in facilitating treatment resistance remains limited. Here we provide a comprehensive summary of the evidence linking autophagy to major signaling pathways in the context of treatment resistance and tumor progression, and then highlight recently emerged molecular mechanisms underlying autophagy and the p62/KEAP1/NRF2 and FOXO3A/PUMA axes in chemoresistance.

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“…Chloroquine promotes Tmz sensitivity by promoting apoptotic cell death while inhibiting autophagosome fusion and mitochondrial autophagy [255]. Hydroxy-chloroquine (5 µg/mL) synergizes Bevacizumab (100 µg/mL) inhibition of autophagy by increasing LC3-II/LC3-I ratio and p62 that causes Beclin1 degradation [256]. The formation of GSCs and the highly hypoxic HGG tumors may hinder current therapy efficacy in HGG.…”

Section: Repurposing Drugs For Hggmentioning

confidence: 99%

Challenges and Perspectives of Standard Therapy and Drug Development in High-Grade Gliomas

et al. 2021

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Despite their low incidence rate globally, high-grade gliomas (HGG) remain a fatal primary brain tumor. The recommended therapy often is incapable of resecting the tumor entirely and exclusively targeting the tumor leads to tumor recurrence and dismal prognosis. Additionally, many HGG patients are not well suited for standard therapy and instead, subjected to a palliative approach. HGG tumors are highly infiltrative and the complex tumor microenvironment as well as high tumor heterogeneity often poses the main challenges towards the standard treatment. Therefore, a one-fit-approach may not be suitable for HGG management. Thus, a multimodal approach of standard therapy with immunotherapy, nanomedicine, repurposing of older drugs, use of phytochemicals, and precision medicine may be more advantageous than a single treatment model. This multimodal approach considers the environmental and genetic factors which could affect the patient’s response to therapy, thus improving their outcome. This review discusses the current views and advances in potential HGG therapeutic approaches and, aims to bridge the existing knowledge gap that will assist in overcoming challenges in HGG.

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Hydroxychloroquine potentiates the anti-cancer effect of bevacizumab on glioblastoma via the inhibition of autophagy

Cited by 35 publications

References 19 publications

Curcumin suppresses LGR5(+) colorectal cancer stem cells by inducing autophagy and via repressing TFAP2A-mediated ECM pathway

Curcumin suppresses LGR5(+) colorectal cancer stem cells by inducing autophagy and via repressing TFAP2A-mediated ECM pathway

Molecular Mechanisms Underlying Autophagy-Mediated Treatment Resistance in Cancer

Challenges and Perspectives of Standard Therapy and Drug Development in High-Grade Gliomas

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