Top

Published in:

01-10-2020 | Pancreatic Cancer | PRECLINICAL STUDIES

Combination of a novel microtubule inhibitor MBRI-001 and gemcitabine synergistically induces cell apoptosis by increasing DNA damage in pancreatic cancer cell lines

Authors: Yuqian Liu, Ruochen Zang, Feifei Li, Chuanqin Shi, Jianchun Zhao, Lili Zhong, Xin Wang, Jinbo Yang, Wenbao Li

Published in: Investigational New Drugs | Issue 5/2020

Summary

Pancreatic cancer (PC) is a highly malignant cancer with poor prognosis. Although gemcitabine (GEM; 2′,2′-difluoro-deoxycytidine) has been used as the first-line chemotherapeutic agent in PC treatment for decades, its limited efficacy remains a significant clinical issue, which may be resolved by GEM combination therapy. In this study, we aimed to investigate the anti-tumor effects of MBRI-001 in combination with GEM in BxPC-3 and MIA PaCa-2 human PC cell lines. In vitro and in vivo results indicate that MBRI-001 showed synergistic activity with GEM. GEM induced apoptosis by increasing DNA damage (phosphorylated core histone protein H2AX (γ-H2AX)), MBRI-001 activated mitochondrial-apoptotic pathway (cleaved poly-ADP ribose polymerase (PARP)). Thus, the combination of the two intensified both apoptosis and DNA damage and showed significantly superior anti-tumor activity compared to each agent alone. The adoption of combination of MBRI-001 with GEM may be beneficial as they act synergistically and thus, can be a potential therapeutic choice for improving the prognosis of PC patients in the future.

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424. https://doi.org/10.3322/caac.21492CrossRef

Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J (2016) Cancer statistics in China, 2015. CA Cancer J Clin 66(2):115–132. https://doi.org/10.3322/caac.21338CrossRefPubMed

Lai X, Wang M, McElyea SD, Sherman S, House M, Korc M (2017) A microRNA signature in circulating exosomes is superior to exosomal glypican-1 levels for diagnosing pancreatic cancer. Cancer Lett 393:86–93. https://doi.org/10.1016/j.canlet.2017.02.019CrossRefPubMedPubMedCentral

Choi M, Bien H, Mofunanya A, Powers S (2019) Challenges in Ras therapeutics in pancreatic cancer. Semin Cancer Biol 54:101–108. https://doi.org/10.1016/j.semcancer.2017.11.015CrossRefPubMed

Yokoyama Y, Nimura Y, Nagino M (2009) Advances in the treatment of pancreatic cancer: limitations of surgery and evaluation of new therapeutic strategies. Surg Today 39(6):466–475. https://doi.org/10.1007/s00595-008-3904-6CrossRefPubMed

Binenbaum Y, Na'ara S, Gil Z (2015) Gemcitabine resistance in pancreatic ductal adenocarcinoma. Drug Resist Updat 23:55–68. https://doi.org/10.1016/j.drup.2015.10.002CrossRefPubMed

Berlin JD, Catalano P, Thomas JP, Kugler JW, Haller DG, Benson AB 3rd (2002) Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: eastern cooperative oncology group trial E2297. J Clin Oncol 20(15):3270–3275. https://doi.org/10.1200/jco.2002.11.149CrossRefPubMed

Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15(6):2403–2413. https://doi.org/10.1200/jco.1997.15.6.2403CrossRefPubMed

Bastiancich C, Bastiat G, Lagarce F (2018) Gemcitabine and glioblastoma: challenges and current perspectives. Drug Discov Today 23(2):416–423. https://doi.org/10.1016/j.drudis.2017.10.010CrossRefPubMed

10.

Heinemann V (2001) Gemcitabine: progress in the treatment of pancreatic cancer. Oncology 60(1):8–18. https://doi.org/10.1159/000055290CrossRefPubMed

11.

Shah AN, Summy JM, Zhang J, Park SI, Parikh NU, Gallick GE (2007) Development and characterization of gemcitabine-resistant pancreatic tumor cells. Ann Surg Oncol 14(12):3629–3637. https://doi.org/10.1245/s10434-007-9583-5CrossRefPubMed

12.

Zhou BB, Bartek J (2004) Targeting the checkpoint kinases: chemosensitization versus chemoprotection. Nat Rev Cancer 4(3):216–225. https://doi.org/10.1038/nrc1296CrossRefPubMed

13.

Kerssemakers JW, Munteanu EL, Laan L, Noetzel TL, Janson ME, Dogterom M (2006) Assembly dynamics of microtubules at molecular resolution. Nature 442(7103):709–712. https://doi.org/10.1038/nature04928CrossRefPubMed

14.

Kavallaris M (2010) Microtubules and resistance to tubulin-binding agents. Nat Rev Cancer 10(3):194–204. https://doi.org/10.1038/nrc2803CrossRefPubMed

15.

Akhmanova A, Hoogenraad CC (2015) Microtubule minus-end-targeting proteins. Curr Biol 25(4):R162–R171. https://doi.org/10.1016/j.cub.2014.12.027CrossRefPubMed

16.

Perez EA (2009) Microtubule inhibitors: differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance. Mol Cancer Ther 8(8):2086–2095. https://doi.org/10.1158/1535-7163.mct-09-0366CrossRefPubMed

17.

McGrogan BT, Gilmartin B, Carney DN, McCann A (2008) Taxanes, microtubules and chemoresistant breast cancer. Biochim Biophys Acta Rev Cancer 1785(2):96–132. https://doi.org/10.1016/j.bbcan.2007.10.004CrossRef

18.

Singh AV, Bandi M, Raje N, Richardson P, Palladino MA, Chauhan D, Anderson KC (2011) A novel vascular disrupting agent plinabulin triggers JNK-mediated apoptosis and inhibits angiogenesis in multiple myeloma cells. Blood 117(21):5692–5700. https://doi.org/10.1182/blood-2010-12-323857CrossRefPubMedPubMedCentral

19.

Ding Z, Cheng H, Wang S, Hou Y, Zhao J, Guan H, Li W (2017) Development of MBRI-001, a deuterium-substituted plinabulin derivative as a potent anti-cancer agent. Bioorg Med Chem Lett 27(6):1416–1419. https://doi.org/10.1016/j.bmcl.2017.01.096CrossRefPubMed

20.

Deng M, Li L, Zhao J, Yuan S, Li W (2018) Antitumor activity of the microtubule inhibitor MBRI-001 against human hepatocellular carcinoma as monotherapy or in combination with sorafenib. Cancer Chemother Pharmacol 81(5):853–862. https://doi.org/10.1007/s00280-018-3547-2CrossRefPubMed

21.

Ashton JC (2015) Drug combination studies and their synergy quantification using the Chou-Talalay method–letter. Cancer Res 75(11):2400. https://doi.org/10.1158/0008-5472.can-14-3763CrossRefPubMed

22.

Mah LJ, El-Osta A, Karagiannis TC (2010) gammaH2AX: a sensitive molecular marker of DNA damage and repair. Leukemia 24(4):679–686. https://doi.org/10.1038/leu.2010.6CrossRefPubMed

23.

de Sousa CL, Monteiro G (2014) Gemcitabine: metabolism and molecular mechanisms of action, sensitivity and chemoresistance in pancreatic cancer. Eur J Pharmacol 741:8–16. https://doi.org/10.1016/j.ejphar.2014.07.041CrossRef

24.

Zhang M, Zhuang G, Sun X, Shen Y, Wang W, Li Q, Di W (2017) TP53 mutation-mediated genomic instability induces the evolution of chemoresistance and recurrence in epithelial ovarian cancer. Diagn Pathol 12(1):16. https://doi.org/10.1186/s13000-017-0605-8CrossRefPubMedPubMedCentral

25.

Kwok M, Davies N, Agathanggelou A, Smith E, Oldreive C, Petermann E, Stewart G, Brown J, Lau A, Pratt G, Parry H, Taylor M, Moss P, Hillmen P, Stankovic T (2016) ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells. Blood 127(5):582–595. https://doi.org/10.1182/blood-2015-05-644872CrossRefPubMed

26.

Kastenhuber ER, Lowe SW (2017) Putting p53 in context. Cell 170(6):1062–1078. https://doi.org/10.1016/j.cell.2017.08.028CrossRefPubMedPubMedCentral

27.

Fiorini C, Cordani M, Padroni C, Blandino G, Di Agostino S, Donadelli M (2015) Mutant p53 stimulates chemoresistance of pancreatic adenocarcinoma cells to gemcitabine. Biochim Biophys Acta Mol Cell Res 1853(1):89–100. https://doi.org/10.1016/j.bbamcr.2014.10.003CrossRef

28.

Kutuk O, Letai A (2008) Alteration of the mitochondrial apoptotic pathway is key to acquired paclitaxel resistance and can be reversed by ABT-737. Cancer Res 68(19):7985–7994. https://doi.org/10.1158/0008-5472.can-08-1418CrossRefPubMedPubMedCentral

29.

Gu F, Li L, Yuan QF, Li C, Li ZH (2017) Down-regulation of survivin enhances paclitaxel-induced Hela cell apoptosis. Eur Rev Med Pharmacol Sci 21(15):3504–3509PubMed

30.

Das GC, Holiday D, Gallardo R, Haas C (2001) Taxol-induced cell cycle arrest and apoptosis: dose-response relationship in lung cancer cells of different wild-type p53 status and under isogenic condition. Cancer Lett 165(2):147–153. https://doi.org/10.1016/s0304-3835(01)00404-9CrossRefPubMed

31.

Goldstein D, El-Maraghi RH, Hammel P, Heinemann V, Kunzmann V, Sastre J, Scheithauer W, Siena S, Tabernero J, Teixeira L, Tortora G, Van Laethem JL, Young R, Penenberg DN, Lu B, Romano A, Von Hoff DD (2015) Nab-paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial. J Natl Cancer Inst 107(2). https://doi.org/10.1093/jnci/dju413

Title: Combination of a novel microtubule inhibitor MBRI-001 and gemcitabine synergistically induces cell apoptosis by increasing DNA damage in pancreatic cancer cell lines
Authors: Yuqian Liu
Ruochen Zang
Feifei Li
Chuanqin Shi
Jianchun Zhao
Lili Zhong
Xin Wang
Jinbo Yang
Wenbao Li
Publication date: 01-10-2020
Publisher: Springer US
Keywords: Pancreatic Cancer
Pancreatic Cancer
Published in: Investigational New Drugs / Issue 5/2020
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-019-00874-5

2024 ASCO Annual Meeting Coverage

Highlights of the Day: Breast cancer – metastatic

Breast Cancer Video

In this session, Dr. Wolff provides his key takeaways from the data presented in the metastatic breast cancer oral abstract session at ASCO 2024.

Watch now

Highlights of the Day: Gynecologic cancer

Gynecologic Cancer Video

Highlights of the Day: Breast Cancer – local/regional/adjuvant

Breast Cancer Video

Neoadjuvant dual immunotherapy improves melanoma outcomes

04-06-2024 Melanoma News

» View more highlights on the ASCO 2024 congress hub page

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Image Credits

ASCO 2024 | Highlights of the Day: Breast cancer – metastatic/© 2024 American Society of Clinical Oncology, all rights reserved., ASCO 2024 | Highlights of the Day: Gynecologic Cancer/© 2024 American Society of Clinical Oncology, all rights reserved., ASCO 2024 | Highlights of the Day: Breast Cancer – local/regional/adjuvant/© 2024 American Society of Clinical Oncology, all rights reserved., Melanoma/© selvanegra / Getty Images / iStock, Antibody drug conjugated with cytotoxic payload/© Love Employee / Getty images / iStock

2024 ASCO Annual Meeting

Springer Medicine

Summary

Please log in to get access to this content

Other articles of this Issue 5/2020

Metabolomic profiling to evaluate the efficacy of proxalutamide, a novel androgen receptor antagonist, in prostate cancer cells

Phase 1 study to evaluate safety, tolerability and pharmacokinetics of a novel intra-tympanic administered thiosulfate to prevent cisplatin-induced hearing loss in cancer patients

Pharmacokinetics of mitomycin-c lipidic prodrug entrapped in liposomes and clinical correlations in metastatic colorectal cancer patients

A randomized, phase 2 study of deoxyuridine triphosphatase inhibitor, TAS-114, in combination with S-1 versus S-1 alone in patients with advanced non-small-cell lung cancer

Retrospective review of the activity and safety of apatinib and anlotinib in patients with advanced osteosarcoma and soft tissue sarcoma