Identification of cisplatin sensitizers through high-throughput combinatorial screening

Sun,Yichen; Jiang,Weiye; Lu,Wenhua; Song,Ming; Liu,Kaiyan; Chen,Ping; Chang,Allison; Ling,Jianhua; Chiao,Paul  J.; Hu,Yumin; Huang,Peng

doi:10.3892/ijo.2018.4447

Identification of cisplatin sensitizers through high-throughput combinatorial screening

Authors:
- Yichen Sun
- Weiye Jiang
- Wenhua Lu
- Ming Song
- Kaiyan Liu
- Ping Chen
- Allison Chang
- Jianhua Ling
- Paul J. Chiao
- Yumin Hu
- Peng Huang
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Affiliations: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China, Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Published online on: June 19, 2018 https://doi.org/10.3892/ijo.2018.4447
Pages: 1237-1246

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Abstract

cis-Diamminedichloroplatinum/cisplatin (CDDP) is a major drug used in cancer chemotherapy; however, the toxic side-effects and development of drug resistance represent major challenges to the clinical use of CDDP. The aim of the present study was to identify effective drug combination regimens through high-throughput drug screening that can enhance the efficacy of CDDP, and to investigate the underlying mechanisms. A cell-based high-throughput screening methodology was implemented, using a library of 1,280 Food and Drug Administration (FDA)-approved drugs, to identify clinical compounds that act synergistically with CDDP. Our study identified two compounds, namely potassium antimony tartrate and topotecan, that significantly enhanced the sensitivity of colorectal and non-small cell lung cancer cells to CDDP. The synergistic action of both compounds with CDDP was confirmed by further quantitative analyses. Topotecan is a topoisomerase-1 inhibitor that has previously been shown to enhance the clinical response and overall patient survival when combined with CDDP by a yet unclear mechanism. We demonstrated that the combination of topotecan with CDDP significantly inhibited colony formation ability and increased the apoptosis of several cancer cell lines. Mechanistic analyses revealed that topotecan enhanced CDDP-induced DNA damage and inhibited the repair of DNA strand breaks, without affecting the cellular platinum content. Overall, the findings of this study demonstrated that the use of the FDA-approved drug panel in high-throughput screening is an effective method for identifying effective therapeutic regimens that are clinically relevant, and may have high feasibility for translation into clinical practice.

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1	Rosenberg B, VanCamp L, Trosko JE and Mansour VH: Platinum compounds: A new class of potent antitumour agents. Nature. 222:385–386. 1969. View Article : Google Scholar : PubMed/NCBI
2	Jamieson ER and Lippard SJ: Structure, recognition, and processing of cisplatin-DNA adducts. Chem Rev. 99:2467–2498. 1999. View Article : Google Scholar
3	Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, Focan C, Chollet P, Llory JF, Letourneau Y, Coudert B, et al: Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 18:136–147. 2000. View Article : Google Scholar : PubMed/NCBI
4	Vasey PA, Paul J, Birt A, Junor EJ, Reed NS, Symonds RP, Atkinson R, Graham J, Crawford SM, Coleman R, et al Scottish Gynaecological Cancer Trials Group: Docetaxel and cisplatin in combination as first-line chemotherapy for advanced epithelial ovarian cancer. J Clin Oncol. 17:2069–2080. 1999. View Article : Google Scholar : PubMed/NCBI
5	Wang D and Lippard SJ: Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov. 4:307–320. 2005. View Article : Google Scholar : PubMed/NCBI
6	Kelland L: The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer. 7:573–584. 2007. View Article : Google Scholar : PubMed/NCBI
7	Santos NA, Catão CS, Martins NM, Curti C, Bianchi ML and Santos AC: Cisplatin-induced nephrotoxicity is associated with oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria. Arch Toxicol. 81:495–504. 2007. View Article : Google Scholar : PubMed/NCBI
8	Dasari S and Tchounwou PB: Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J Pharmacol. 740:364–378. 2014. View Article : Google Scholar : PubMed/NCBI
9	Macciò A and Madeddu C: Cisplatin : An old drug with a newfound efficacy - from mechanisms of action to cytotoxicity. Expert Opin Pharmacother. 14:1839–1857. 2013. View Article : Google Scholar
10	Holohan C, Van Schaeybroeck S, Longley DB and Johnston PG: Cancer drug resistance: An evolving paradigm. Nat Rev Cancer. 13:714–726. 2013. View Article : Google Scholar : PubMed/NCBI
11	Kelland LR, Sharp SY, O'Neill CF, Raynaud FI, Beale PJ and Judson IR: Mini-review: Discovery and development of platinum complexes designed to circumvent cisplatin resistance. J Inorg Biochem. 77:111–115. 1999. View Article : Google Scholar
12	Wong E and Giandomenico CM: Current status of platinum-based antitumor drugs. Chem Rev. 99:2451–2466. 1999. View Article : Google Scholar
13	Martín M: Platinum compounds in the treatment of advanced breast cancer. Clin Breast Cancer. 2:190–209. 2001. View Article : Google Scholar
14	Cosaert J and Quoix E: Platinum drugs in the treatment of non-small-cell lung cancer. Br J Cancer. 87:825–833. 2002. View Article : Google Scholar : PubMed/NCBI
15	Al-Lazikani B, Banerji U and Workman P: Combinatorial drug therapy for cancer in the post-genomic era. Nat Biotechnol. 30:679–692. 2012. View Article : Google Scholar : PubMed/NCBI
16	Chong CR and Sullivan DJ Jr: New uses for old drugs. Nature. 448:645–646. 2007. View Article : Google Scholar : PubMed/NCBI
17	Weir SJ, DeGennaro LJ and Austin CP: Repurposing approved and abandoned drugs for the treatment and prevention of cancer through public-private partnership. Cancer Res. 72:1055–1058. 2012. View Article : Google Scholar : PubMed/NCBI
18	Pessetto ZY, Weir SJ, Sethi G, Broward MA and Godwin AK: Drug repurposing for gastrointestinal stromal tumor. Mol Cancer Ther. 12:1299–1309. 2013. View Article : Google Scholar : PubMed/NCBI
19	Chou TC: Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 70:440–446. 2010. View Article : Google Scholar : PubMed/NCBI
20	Mathews Griner LA, Guha R, Shinn P, Young RM, Keller JM, Liu D, Goldlust IS, Yasgar A, McKnight C, Boxer MB, et al: High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell-like diffuse large B-cell lymphoma cells. Proc Natl Acad Sci USA. 111:2349–2354. 2014. View Article : Google Scholar : PubMed/NCBI
21	Yuan S, Wang F, Chen G, Zhang H, Feng L, Wang L, Colman H, Keating MJ, Li X, Xu RH, et al: Effective elimination of cancer stem cells by a novel drug combination strategy. Stem Cells. 31:23–34. 2013. View Article : Google Scholar :
22	Di Pasqua AJ, Hong C, Wu MY, McCracken E, Wang X, Mi L and Chung FL: Sensitization of non-small cell lung cancer cells to cisplatin by naturally occurring isothiocyanates. Chem Res Toxicol. 23:1307–1309. 2010. View Article : Google Scholar : PubMed/NCBI
23	Spigel DR and Greco FA: Chemotherapy in metastatic and locally advanced non-small cell lung cancer. Semin Surg Oncol. 21:98–110. 2003. View Article : Google Scholar : PubMed/NCBI
24	Hata F, Sasaki K, Hirata K, Yamamitsu S and Shirasaka T: Efficacy of a continuous venous infusion of fluorouracil and daily divided dose cisplatin as adjuvant therapy in resectable colorectal cancer: A prospective randomized trial. Surg Today. 38:623–632. 2008. View Article : Google Scholar : PubMed/NCBI
25	Pommier Y: Topoisomerase I inhibitors: Camptothecins and beyond. Nat Rev Cancer. 6:789–802. 2006. View Article : Google Scholar : PubMed/NCBI
26	Wang JC: Cellular roles of DNA topoisomerases: A molecular perspective. Nat Rev Mol Cell Biol. 3:430–440. 2002. View Article : Google Scholar : PubMed/NCBI
27	Staker BL, Hjerrild K, Feese MD, Behnke CA, Burgin AB Jr and Stewart L: The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc Natl Acad Sci USA. 99:15387–15392. 2002. View Article : Google Scholar : PubMed/NCBI
28	Redon C, Pilch D, Rogakou E, Sedelnikova O, Newrock K and Bonner W: Histone H2A variants H2AX and H2AZ. Curr Opin Genet Dev. 12:162–169. 2002. View Article : Google Scholar : PubMed/NCBI
29	Furuta T, Takemura H, Liao ZY, Aune GJ, Redon C, Sedelnikova OA, Pilch DR, Rogakou EP, Celeste A, Chen HT, et al: Phosphorylation of histone H2AX and activation of Mre11, Rad50, and Nbs1 in response to replication-dependent DNA double-strand breaks induced by mammalian DNA topoisomerase I cleavage complexes. J Biol Chem. 278:20303–20312. 2003. View Article : Google Scholar : PubMed/NCBI
30	Costa RM, Chiganças V, Galhardo RS, Carvalho H and Menck CF: The eukaryotic nucleotide excision repair pathway. Biochimie. 85:1083–1099. 2003. View Article : Google Scholar
31	Komuro Y, Udagawa Y, Susumu N, Aoki D, Kubota T and Nozawa S: Paclitaxel and SN-38 overcome cisplatin resistance of ovarian cancer cell lines by down-regulating the influx and efflux system of cisplatin. Jpn J Cancer Res. 92:1242–1250. 2001. View Article : Google Scholar : PubMed/NCBI
32	Stordal B, Pavlakis N and Davey R: Oxaliplatin for the treatment of cisplatin-resistant cancer: A systematic review. Cancer Treat Rev. 33:347–357. 2007. View Article : Google Scholar : PubMed/NCBI
33	Terakawa T, Miyake H, Yokoyama N, Miyazaki A, Tanaka H, Inoue T and Fujisawa M: Clinical outcome of paclitaxel and carboplatin as second-line chemotherapy for advanced urothelial carcinoma resistant to first-line therapy with gemcitabine and cisplatin. Urol Int. 92:180–185. 2014. View Article : Google Scholar
34	Small BG, McColl BW, Allmendinger R, Pahle J, López-Castejón G, Rothwell NJ, Knowles J, Mendes P, Brough D and Kell DB: Efficient discovery of anti-inflammatory small- molecule combinations using evolutionary computing. Nat Chem Biol. 7:902–908. 2011. View Article : Google Scholar : PubMed/NCBI
35	Pignata S, Cannella L, Leopardo D, Pisano C, Bruni GS and Facchini G: Chemotherapy in epithelial ovarian cancer. Cancer Lett. 303:73–83. 2011. View Article : Google Scholar : PubMed/NCBI
36	Murray HW, Pépin J, Nutman TB, Hoffman SL and Mahmoud AA: Tropical medicine. BMJ. 320:490–494. 2000. View Article : Google Scholar : PubMed/NCBI
37	Schulert AR, Rassoul AA, Mansour M, Girgis N, McConnell E and Farid Z: Biological disposition of antibilharzial antimony drugs. II. Antimony fate and uptake by Schistosoma haematobium eggs in man. Exp Parasitol. 18:397–402. 1966. View Article : Google Scholar : PubMed/NCBI
38	Duffin J and Campling BG: Therapy and disease concepts: The history (and future?) of antimony in cancer. J Hist Med Allied Sci. 57:61–78. 2002. View Article : Google Scholar : PubMed/NCBI
39	Lecureur V, Lagadic-Gossmann D and Fardel O: Potassium antimonyl tartrate induces reactive oxygen species-related apoptosis in human myeloid leukemic HL60 cells. Int J Oncol. 20:1071–1076. 2002.PubMed/NCBI
40	Lecureur V, Le Thiec A, Le Meur A, Amiot L, Drenou B, Bernard M, Lamy T, Fauchet R and Fardel O: Potassium antimonyl tartrate induces caspase- and reactive oxygen species-dependent apoptosis in lymphoid tumoral cells. Br J Haematol. 119:608–615. 2002. View Article : Google Scholar : PubMed/NCBI
41	Wang B, Yu W, Guo J, Jiang X, Lu W, Liu M and Pang X: The antiparasitic drug, potassium antimony tartrate, inhibits tumor angiogenesis and tumor growth in nonsmall-cell lung cancer. J Pharmacol Exp Ther. 352:129–138. 2015. View Article : Google Scholar
42	Weiss S and Hatcher RA: The mechanism of the vomiting induced by antimony and Potassium tartrate (Tartar emetic). J Exp Med. 37:97–111. 1923. View Article : Google Scholar : PubMed/NCBI
43	Haldar AK, Sen P and Roy S: Use of antimony in the treatment of leishmaniasis: Current status and future directions. Mol Biol Int. 2011:5712422011. View Article : Google Scholar : PubMed/NCBI
44	Robati M, Holtz D and Dunton CJ: A review of topotecan in combination chemotherapy for advanced cervical cancer. Ther Clin Risk Manag. 4:213–218. 2008. View Article : Google Scholar : PubMed/NCBI
45	Riemsma R, Simons JP, Bashir Z, Gooch CL and Kleijnen J: Systematic review of topotecan (Hycamtin) in relapsed small cell lung cancer. BMC Cancer. 10:4362010. View Article : Google Scholar : PubMed/NCBI
46	Boabang P, Kurbacher CM, Kohlhagen H, Waida A and Amo-Takyi BK: Anti-neoplastic activity of topotecan versus cisplatin, etoposide and paclitaxel in four squamous cell cancer cell lines of the female genital tract using an ATP-tumor chemo-sensitivity assay. Anticancer Drugs. 11:843–848. 2000. View Article : Google Scholar
47	Chou TC, Motzer RJ, Tong Y and Bosl GJ: Computerized quantitation of synergism and antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: A rational approach to clinical protocol design. J Natl Cancer Inst. 86:1517–1524. 1994. View Article : Google Scholar : PubMed/NCBI
48	Fiorica JV: The role of topotecan in the treatment of advanced cervical cancer. Gynecol Oncol. 90:S16–S21. 2003. View Article : Google Scholar : PubMed/NCBI
49	Brave M, Dagher R, Farrell A, Abraham S, Ramchandani R, Gobburu J, Booth B, Jiang X, Sridhara R, Justice R, et al: Topotecan in combination with cisplatin for the treatment of stage IVB, recurrent, or persistent cervical cancer. Oncology. 20:1401–1404. 1410–1411. 1415–1406. 2006.PubMed/NCBI