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Drug repurposing screening identifies bortezomib and panobinostat as drugs targeting cancer associated fibroblasts (CAFs) by synergistic induction of apoptosis

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Summary

Cancer associated fibroblasts (CAFs) are the most abundant components of cancer-microenvironment. They play important roles in cancer initiation, progression, and metastasis. In addition, CAFs can confer drug-resistance to cancer cells. Considering their pro-tumorigenic roles, it is recommended to remove CAFs to prevent cancer recurrence after chemotherapy. Despite their clinical significance, few anti-CAF drugs have been developed. The objective of this study was to find a drug that could suppress the viability of patient-derived CAFs through repurposed screening of 51 drugs that were in clinical trials or received FDA approval. As a result, bortezomib (BTZ), carfilzomib (CFZ), and panobinostat (PST) were identified as anti-CAF drug candidates. It was confirmed that BTZ and PST could decrease the viability of various patients derived CAFs through inducing of caspase-3 mediated apoptosis. Interestingly, combination therapy with BTZ and PST showed better efficacy of inhibiting CAFs than single treatment. The synergistic effect between BTZ and PST on viability of CAFs was observed both in vitro CAF culture and in vivo mouse model. Furthermore, combination therapy with BTZ/PST and conventional anticancer compound docetaxel strongly inhibited tumor growth in xenografts of mouse breast cancer cells with mouse CAFs. In conclusion, our present study revealed that BTZ and PST could significantly reduce the viability of CAFs. Therefore, a combination therapy with BTZ/PST and anticancer drugs might be considered as a new rational for the development of anticancer therapy.

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Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2015R1A2A1A15054021) and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C2517).

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Author notes

  1. Hak-Min Lee, Eunmyong Lee and So-Young Yeo contributed equally to this work, as first authors.

Authors and Affiliations

  1. Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

    Hak-Min Lee, So-Young Yeo & Seok-Hyung Kim

  2. Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea

    Hak-Min Lee, So-Young Yeo, Sang Shin, Hyun-Kyu Park, Do-Hyun Nam & Seok-Hyung Kim

  3. Samsung Biomedical Research Institute, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

    Eunmyong Lee

  4. Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

    Sang Shin, Hyun-Kyu Park & Do-Hyun Nam

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  1. Hak-Min Lee
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  2. Eunmyong Lee
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Correspondence to Do-Hyun Nam or Seok-Hyung Kim.

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Conflict of interest

Hak-Min Lee declares that he has no conflict of interest. Eunmyong Lee declares that she has no conflict of interest. So-Young Yeo declares that she has no conflict of interest. Sang Shin declares that he has no conflict of interest. Hyun-Kyu Park declares that he has no conflict of interest. Do-Hyun Nam declares that he has no conflict of interest. Seok-Hyung Kim declares that he has no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of Samsung Medical Center at Sungkyunkwan University, where the studies were conducted.

Electronic supplementary material

Supplementary Fig. 1

Combination treatment of bortezomib and panobinostat attenuates the growth of mouse breast cancer cells and CAFs. (a) Representative photograph of gross tumors from xenografts model with cancer cells alone or cancer cells with MMTV-CAF. Either 5 x 105of 168FARN cells alone or with 1.5 × 106 MMTV-CAFs were subcutaneously injected nude mice. (b) Tumor volumes in xenografts model of 168FARN mouse breast cancer cells alone or with MMTV-CAF at a ratio of 1:1 (n = 4 per group). Tumor volumes were measured using a caliper. Difference was evaluated by two- tailed student’s t-test. * P < 0.05. (c-d) Effect of either BTZ or PST alone or in combination treatment on 168FARN mouse breast cancer cells (c) or mouse MMTV-CAF cells (d). 168FARN cells or MMTV-CAF cells were plated and treated with BTZ (left panels), PST (middle panels), or both (right panels) for 2 days. Cell viability was calculated as a percentage to the control. Experiments were done in triplicates. Symbols represent mean ± SEM. (PPTX 324 kb)

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Lee, HM., Lee, E., Yeo, SY. et al. Drug repurposing screening identifies bortezomib and panobinostat as drugs targeting cancer associated fibroblasts (CAFs) by synergistic induction of apoptosis. Invest New Drugs 36, 545–560 (2018). https://doi.org/10.1007/s10637-017-0547-8

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  • DOI: https://doi.org/10.1007/s10637-017-0547-8

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