17-(Allylamino)-17-Demethoxygeldanamycin Enhances Etoposide-Induced Cytotoxicity via the Downregulation of Xeroderma Pigmentosum Complementation Group C Expression in Human Lung Squamous Cell Carcinoma Cells

Chen, Jyh-Cheng; Ma, Peng-Fang; Lin, Yuan-Cheng; Wu, Chia-Hung; Peng, Yi-Shuan; Zheng, Hongchao; Lin, Mu-Chuan; Li, Ya-tang

doi:10.1159/000490256

Cited by 2 publications

(3 citation statements)

References 38 publications

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“…Our previous study showed that XPC knockdown by siRNA transfection or cotreatment with 17-AAG sensitizes NSCLC cells to cytotoxicity induced by etoposide [10]. We hypothesized that 17-AAG would affect XPC expression in bevacizumab-treated NSCLC cells.…”

Section: Resultsmentioning

confidence: 99%

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Downregulation of Xeroderma Pigmentosum Complementation Group C Expression by 17-Allylamino-17-Demethoxygeldanamycin Enhances Bevacizumab-Induced Cytotoxicity in Human Lung Cancer Cells

Chen

Taso

et al. 2020

Pharmacology

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Introduction: Xeroderma pigmentosum complementation group C (XPC) protein is an important DNA damage recognition factor involved in nucleotide excision repair and regulation of non-small-cell lung cancer (NSCLC) cell proliferation and viability. 17-Allylamino-17-demethoxygeldanamycin (17-AAG) blocks ATP binding to heat shock protein 90 (Hsp90), resulting in destabilization of Hsp90-client protein complexes. Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor expressed by many types of tumors. Bevacizumab (Avastin) is a humanized monoclonal antibody against human VEGF used as an antiangiogenesis agent in the therapy of many cancers, proving successful in increasing objective tumor response rate and prolonging overall survival in NSCLC patients. Methods: After the bevacizumab and/or 17-AAG treatment, the expressions of XPC mRNA were determined by quantitative real-time PCR analysis. Protein levels of XPC and phospho-AKT were determined by Western blot analysis. We used specific XPC small interfering RNA and PI3K inhibitor (LY294002) to examine the role of the AKT-XPC signal in regulating the chemosensitivity of bevacizumab and 17-AAG. Cell viability was assessed by the MTS assay and trypan blue exclusion assay. Results: In this study, bevacizumab decreased XPC expression in human lung squamous cell carcinoma H520 and H1703 cells via AKT inactivation. Enhancement of AKT activity by transfection with constitutively active AKT vectors increased XPC expression and cell survival after treatment with bevacizumab. In addition, 17-AAG synergistically enhanced bevacizumab-induced cytotoxicity and cell growth inhibition in H520 and H1703 cells, associated with downregulation of XPC expression and inactivation of AKT. Discussion/Conclusion: Together, these results may provide a rationale to combine bevacizumab with Hsp90 inhibitors in future to enhance therapeutic effects for lung cancer.

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Section: Resultsmentioning

confidence: 99%

“…In human HaCaT keratinocytes, loss of PTEN decreases XPC expression through AKT and p38 signaling [9]. Interestingly, however, in human lung cancer cells, XPC knockdown using siRNA enhances the cytotoxic effects of etoposide [10].…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Xeroderma Pigmentosum Complementation Group C Expression by 17-Allylamino-17-Demethoxygeldanamycin Enhances Bevacizumab-Induced Cytotoxicity in Human Lung Cancer Cells

Chen

Taso

et al. 2020

Pharmacology

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“…However, both exhibit sustained and highly induced expressions in tumor cells, so both are important antitumor targets. However, current clinical treatment using Topo II or Hsp90 inhibitors alone is not sufficiently ideal, and combined drug research shows that Topo II poisons and Hsp90 inhibitors have a synergistic effect in tumor treatment [ 20 , 21 , 22 , 23 , 24 ]. There is a certain correlation between Topo II and Hsp90 in tumor treatment.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Quinacrine as a Potent Topo II and Hsp90 Dual-Target Inhibitor, Repurposing for Cancer Therapy

et al. 2022

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Topo II and Hsp90 are promising targets. In this study, we first verified the structural similarities between Topo IIα ATPase and Hsp90α N−ATPase. Subsequently, 720 compounds from the Food and Drug Administration (FDA) drug library and kinase library were screened using the malachite green phosphate combination with the Topo II-mediated DNA relaxation and MTT assays. Subsequently, the antimalarial drug quinacrine was found to be a potential dual−target inhibitor of Topo II and Hsp90. Mechanistic studies showed that quinacrine could specifically bind to the Topo IIα ATPase domain and inhibit the activity of Topo IIα ATPase without impacting DNA cleavage. Furthermore, our study revealed that quinacrine could bind Hsp90 N−ATPase and inhibit Hsp90 activity. Significantly, quinacrine has broad antiproliferation activity and remains sensitive to the multidrug−resistant cell line MCF−7/ADR and the atypical drug−resistant tumor cell line HL−60/MX2. Our study identified quinacrine as a potential dual−target inhibitor of Topo II and Hsp90, depending on the ATP−binding domain, positioning it as a hit compound for further structural modification.

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17-(Allylamino)-17-Demethoxygeldanamycin Enhances Etoposide-Induced Cytotoxicity via the Downregulation of Xeroderma Pigmentosum Complementation Group C Expression in Human Lung Squamous Cell Carcinoma Cells

Cited by 2 publications

References 38 publications

Downregulation of Xeroderma Pigmentosum Complementation Group C Expression by 17-Allylamino-17-Demethoxygeldanamycin Enhances Bevacizumab-Induced Cytotoxicity in Human Lung Cancer Cells

Downregulation of Xeroderma Pigmentosum Complementation Group C Expression by 17-Allylamino-17-Demethoxygeldanamycin Enhances Bevacizumab-Induced Cytotoxicity in Human Lung Cancer Cells

Discovery of Quinacrine as a Potent Topo II and Hsp90 Dual-Target Inhibitor, Repurposing for Cancer Therapy

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