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CUDC-907, a dual HDAC and PI3K inhibitor, reverses platinum drug resistance

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Summary

Platinum (Pt)-based anticancer drugs are the mainstay of treatment for solid cancers. However, resistance to Pt drugs develops rapidly, which can be caused by overexpression of multidrug resistance transporters and activation of DNA repair. CUDC-907 is a potent molecular targeted anticancer agent, rationally designed to simultaneously inhibit histone deacetylase (HDAC) and phosphatidylinositol 3-kinase (PI3K). We investigated the potentiation effect of CUDC-907 on Pt drugs in resistant cancer cells. ABCC2 stably-transfected HEK293 cells and two pairs of parental and Pt-resistant cancer cell lines were used to test for the circumvention of resistance by CUDC-907. Chemosensitivity was assessed by the sulphorhodamine B assay. Drug combinations were evaluated by the median effect analysis. ABCC2 transport activity was examined by flow cytometric assay. Cellular Pt drug accumulation and DNA platination were detected by inductively coupled plasma optical emission spectroscopy. ABCC2, ERCC1 and p21 expression were evaluated by quantitative real-time PCR. Cell cycle analysis and apoptosis assay were performed by standard flow cytometric method. The combination of CUDC-907 with cisplatin were found to exhibit synergistic cytotoxic effect in cisplatin-resistant cancer cells. In Pt-resistant cancer cells, CUDC-907 apparently circumvented the resistance through inhibition of ABCC2 and DNA repair but induction of cell cycle arrest. In the presence of CUDC-907, cellular accumulation of Pt drugs and formation of DNA-Pt adducts were found to be increased whereas expression levels of ABCC2 and ERCC1 was inhibited in Pt-resistant cells. The data advocates further development of CUDC-907 as a resistance reversal agent for use in combination cancer chemotherapy.

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Abbreviations

ABC:

ATP-Binding Cassette

BB:

Benzbromarone

CFDA:

Carboxy-2′,7′-dichlorofluorescein

CI:

Combination Index

HDAC:

Histone Deacetylase

ICP-OES:

Inductively Coupled Plasma Optical Emission Spectrometer

MDR:

Multidrug Resistance

PI3K:

Phosphatidylinositol 3-kinase

Pt:

Platinum

TKI:

Tyrosine Kinase Inhibitor

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Acknowledgements

We would like to thank Dr. Michael Gottesman (National Cancer Institute, NIH), Dr. Susan Bates (National Cancer Institute, NIH), and Prof. Cho Chi Hin (School of Biomedical Sciences, The Chinese University of Hong Kong) for the cell lines employed in the study.

Funding

The work was supported by the NSFC/RGC Joint Research Scheme 2010/11 sponsored by the Research Grants Council of Hong Kong and the National Natural Science Foundation of China (Project No. N_CUHK443/10) and the CUHK Direct Grant for Research (4054296).

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Authors and Affiliations

  1. School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Room 801N, Area 39, Lo Kwee-Seong Integrated Biomedical Sciences Building, Shatin, New Territories, Hong Kong, SAR, China

    Kenneth K. W. To

  2. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-Sen University, Guangzhou, Guangdong, 510060, China

    Li-wu Fu

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  1. Kenneth K. W. To
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Correspondence to Kenneth K. W. To.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Electronic supplementary material

Supplementary Fig. 1

CUDC-907 sensitized cisplatin-resistant HKESC-1 cisR cells to apoptosis. (A) Cells were exposed to cisplatin alone (5 μM), CUDC-907 alone (20 nM), or their combination for 48 h before harvest for apoptosis assay. A representative set of data from three independent experiments is shown. (B) Summary of apoptosis assay data in (A) from three independent experiments. Data are presented in histogram as means ± SD. (TIFF 157 kb)

High Resolution Image (GIF 152 kb)

Supplementary Fig. 2

CUDC-907 increased cellular accumulation of cisplatin in cisplatin-resistant HKESC-1 cisR cells by downregulating ABCC2 expression. (Top panel) Cisplatin accumulation in CUDC-907-treated HKESC-1 and HKESC-1 cisR cells. There was a remarkable reduction in cisplatin accumulation in HKESC-1 cisR cells, relative to the parental HKESC-1 cells. (Bottom panel) Quantitative real-time PCR analysis of ABCC2 mRNA expression in CUDC-907 treated HKESC-1 and HKESC-1 cisR cells. The value in HKESC-1 cells without CUDC-907 treatment was set as 1 for comparison. The mean value from three independent experiments is shown. * p < 0.05, ** p < 0.01, compared with untreated HKESC-1 cisR cells. (TIFF 81 kb)

High Resolution Image (GIF 110 kb)

Supplementary Fig. 3

CUDC-907 increased DNA platination in cisplatin-treated HKESC-1 cisR cells by downregulating ERCC1 expression. (Top panel) DNA platination in HKESC-1 and HKESC-1 cisR cells treated with combination of cisplatin (100 μM) and different concentrations of CUDC-907. There was a significant decrease in DNA platination in cisplatin-resistant HKESC-1 cisR cells, relative to the parental HKESC-1 cells. (Bottom panel) Quantitative real-time PCR analysis of ERCC1 expression in CUDC-907-treated HKESC-1 and HKESC-1 cisR cells. The value in HKESC-1 without CUDC-907 treatment was set as 1 for comparison. The mean value from three independent experiments is shown. * p < 0.05, ** p < 0.01, compared with untreated HKESC-1 cisR cells. (TIFF 80 kb)

High Resolution Image (GIF 110 kb)

Supplementary Fig. 4

Cell cycle analysis in parental HKESC-1 and cisplatin-resistant HKESC-1 cisR cells after cisplatin or CUDC-907 alone or their combination. Summary of cell cycle analysis results from three independent experiments. Data are presented in histograms as mean ± SD; * p < 0.01, versus no treatment in cisplatin-resistant HKESC-1 cisR cells. (TIFF 72 kb)

High Resolution Image (GIF 106 kb)

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To, K.K.W., Fu, Lw. CUDC-907, a dual HDAC and PI3K inhibitor, reverses platinum drug resistance. Invest New Drugs 36, 10–19 (2018). https://doi.org/10.1007/s10637-017-0501-9

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