Advertisement

Investigational New Drugs

, Volume 37, Issue 5, pp 948–960 | Cite as

Sensitization of colorectal cancer to irinotecan therapy by PARP inhibitor rucaparib

  • Titto Augustine
  • Radhashree Maitra
  • Jinghang Zhang
  • Jay Nayak
  • Sanjay GoelEmail author
PRECLINICAL STUDIES

Summary

Intended to explore synthetic lethality and develop better combinatorial regimens, we screened colorectal cancer (CRC) cells using poly ADP-ribose (PAR) polymerase (PARP) inhibitors and cytotoxic agents. We studied four PARP inhibitors and three DNA-damaging agents, and their combinations using sulforhodamine B assay. Rucaparib demonstrated the greatest synergy with irinotecan, followed by olaparib and PJ34. Rucaparib and irinotecan was further subjected to detailed examination to determine combination index (CI) and underlying mechanism of action. Effectiveness and sequence dependence of this combination were assessed in microsatellite stable (MSS) and unstable (MSI) CRC and HCT116 isogenic cell lines. The degree of cell cycle arrest and apoptosis was determined by FACS. In vivo studies were performed to confirm efficacy of this combination. PAR levels in MSI and PARP expression in MSI and MSS cell lines were diminished upon combinatorial treatment. HCT116 isogenic cells revealed the importance of p21, p53 and PTEN in exerting synergy. In MSI cells, administration of rucaparib prior to irinotecan enhanced cytotoxicity compared to other strategies explored. FACS revealed S-phase arrest and increased late-stage apoptosis in MSS, and G2-M arrest and total and early-stage apoptosis in MSI cells. In in vivo murine xenograft models, a significant reduction in tumor volume and expression of Ki67, pancytokeratin and RPS6KB1, and increase in expression of caspase 3 were observed with the combination. In conclusion, among the various combinations studied, rucaparib plus irinotecan was the most synergistic one. Alterations in cell cycle arrest and apoptosis were dependent on MSI status in CRC cells.

Keywords

PARP Rucaparib Irinotecan Colorectal cancer Combinatorial Synergy 

Notes

Acknowledgements

S. Goel is supported by a K-12 award from the National Cancer Institute of the National Institutes of Health 1K12CA132783-01A1, and an Advanced Clinical Research Award (ACRA) in colon cancer, by the ASCO (now Conquer) Cancer Foundation. The authors would like to thank Dr. Tanya Dragic from Department of Microbiology & Immunology, Dr. Balazs Halmos from Department of Medicine and Dr. Thomas J. Ow from Department of Pathology, Albert Einstein College of Medicine/Montefiore Medical Center for their helpful advice on various technical issues examined in this paper, and Dr. Dhanonjoy C. Saha from Office of Grant Support, Albert Einstein College of Medicine, for his advice and comments. The authors also greatly appreciate the expert advice/assistance of Hillary Guzik, Analytical Imaging Facility, Albert Einstein College of Medicine in microscopy/IHC studies. The imaging was conducted in the Analytical Imaging Facility, which is funded by the NCI Cancer Grant P30CA013330.

Funding

The work was supported by the K-12 award from the National Cancer Institute of the National Institutes of Health 1K12CA132783-01A1, and an Advanced Clinical Research Award (ACRA) in colon cancer, by the ASCO (now Conquer) Cancer Foundation to Dr. Sanjay Goel.

Compliance with ethical standards

Conflict of interest

Titto Augustine declares that he has no conflict of interest. Radhashree Maitra declares that she has no conflict of interest. Jinghang Zhang declares that she has no conflict of interest. Jay Nayak declares that he has no conflict of interest. Sanjay Goel declares that he has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants. All applicable institutional guidelines (by Institutional Animal Care and Use Committee) for the care and use of animals were followed.

References

  1. 1.
    Lin YL, Liau JY, Yu SC, Ou DL, Lin LI, Tseng LH, Chang YL, Yeh KH, Cheng AL (2012) KRAS mutation is a predictor of oxaliplatin sensitivity in colon cancer cells. PLoS One 7(11):e50701.  https://doi.org/10.1371/journal.pone.0050701 CrossRefGoogle Scholar
  2. 2.
    Peters GJ (2015) Therapeutic potential of TAS-102 in the treatment of gastrointestinal malignancies. Ther Adv Med Oncol 7(6):340–356.  https://doi.org/10.1177/1758834015603313 CrossRefGoogle Scholar
  3. 3.
    Platell C, Ng S, O'Bichere A, Tebbutt N (2011) Changing management and survival in patients with stage IV colorectal cancer. Dis Colon Rectum 54(2):214–219.  https://doi.org/10.1007/DCR.0b013e3182023bb0 CrossRefGoogle Scholar
  4. 4.
    Rabik CA, Dolan ME (2007) Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev 33(1):9–23.  https://doi.org/10.1016/j.ctrv.2006.09.006 CrossRefGoogle Scholar
  5. 5.
    Osoegawa A, Gills JJ, Kawabata S, Dennis PA (2017) Rapamycin sensitizes cancer cells to growth inhibition by the PARP inhibitor olaparib. Oncotarget 8(50):87044–87053.  https://doi.org/10.18632/oncotarget.19667 CrossRefGoogle Scholar
  6. 6.
    Wei H, Yu X (2016) Functions of PARylation in DNA damage repair pathways. Genomics Proteomics Bioinformatics 14(3):131–139.  https://doi.org/10.1016/j.gpb.2016.05.001 CrossRefGoogle Scholar
  7. 7.
    Dizdar O, Arslan C, Altundag K (2015) Advances in PARP inhibitors for the treatment of breast cancer. Expert Opin Pharmacother 16(18):2751–2758.  https://doi.org/10.1517/14656566.2015.1100168 CrossRefGoogle Scholar
  8. 8.
    Munoz-Gamez JA, Martin-Oliva D, Aguilar-Quesada R, Canuelo A, Nunez MI, Valenzuela MT, Ruiz de Almodovar JM, De Murcia G, Oliver FJ (2005) PARP inhibition sensitizes p53-deficient breast cancer cells to doxorubicin-induced apoptosis. Biochem J 386(Pt 1):119–125.  https://doi.org/10.1042/BJ20040776 CrossRefGoogle Scholar
  9. 9.
    Walsh C (2018) Targeted therapy for ovarian cancer: the rapidly evolving landscape of PARP inhibitor use. Minerva Ginecol 70(2):150–170.  https://doi.org/10.23736/S0026-4784.17.04152-1 Google Scholar
  10. 10.
    Foucquier J, Guedj M (2015) Analysis of drug combinations: current methodological landscape. Pharmacol Res Perspect 3(3):e00149.  https://doi.org/10.1002/prp2.149 CrossRefGoogle Scholar
  11. 11.
    Murai J, Zhang Y, Morris J, Ji J, Takeda S, Doroshow JH, Pommier Y (2014) Rationale for poly(ADP-ribose) polymerase (PARP) inhibitors in combination therapy with camptothecins or temozolomide based on PARP trapping versus catalytic inhibition. J Pharmacol Exp Ther 349(3):408–416.  https://doi.org/10.1124/jpet.113.210146 CrossRefGoogle Scholar
  12. 12.
    Augustine TA, Baig M, Sood A, Budagov T, Atzmon G, Mariadason JM, Aparo S, Maitra R, Goel S (2015) Telomere length is a novel predictive biomarker of sensitivity to anti-EGFR therapy in metastatic colorectal cancer. Br J Cancer 112(2):313–318.  https://doi.org/10.1038/bjc.2014.561 CrossRefGoogle Scholar
  13. 13.
    Gandhi JS, Goswami M, Sharma A, Tanwar P, Gupta G, Gupta N, Pasricha S, Mehta A, Singh S, Agarwal M, Gupta N (2017) Clinical impact of mismatch repair protein testing on outcome of early staged colorectal carcinomas. J Gastrointest Cancer 49:406–414.  https://doi.org/10.1007/s12029-017-9954-5 CrossRefGoogle Scholar
  14. 14.
    Shirasawa S, Furuse M, Yokoyama N, Sasazuki T (1993) Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. Science 260(5104):85–88CrossRefGoogle Scholar
  15. 15.
    Samuels Y, Diaz LA Jr, Schmidt-Kittler O, Cummins JM, Delong L, Cheong I, Rago C, Huso DL, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE (2005) Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7(6):561–573.  https://doi.org/10.1016/j.ccr.2005.05.014 CrossRefGoogle Scholar
  16. 16.
    Jhawer M, Goel S, Wilson AJ, Montagna C, Ling YH, Byun DS, Nasser S, Arango D, Shin J, Klampfer L, Augenlicht LH, Perez-Soler R, Mariadason JM (2008) PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res 68(6):1953–1961.  https://doi.org/10.1158/0008-5472.CAN-07-5659 CrossRefGoogle Scholar
  17. 17.
    Ross DT, Scherf U, Eisen MB, Perou CM, Rees C, Spellman P, Iyer V, Jeffrey SS, Van de Rijn M, Waltham M, Pergamenschikov A, Lee JC, Lashkari D, Shalon D, Myers TG, Weinstein JN, Botstein D, Brown PO (2000) Systematic variation in gene expression patterns in human cancer cell lines. Nat Genet 24(3):227–235.  https://doi.org/10.1038/73432 CrossRefGoogle Scholar
  18. 18.
    Samaraweera L, Adomako A, Rodriguez-Gabin A, McDaid HM (2017) A novel indication for panobinostat as a senolytic drug in NSCLC and HNSCC. Sci Rep 7(1):1900.  https://doi.org/10.1038/s41598-017-01964-1 CrossRefGoogle Scholar
  19. 19.
    Chou TC (2010) Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 70(2):440–446.  https://doi.org/10.1158/0008-5472.CAN-09-1947 CrossRefGoogle Scholar
  20. 20.
    Qin Y, Qi N, Tang Y, He J, Li X, Gu F, Zou S (2015) Isolation and identification of a high molecular weight protein in sow milk. Animal 9(5):847–854.  https://doi.org/10.1017/S1751731114003280 CrossRefGoogle Scholar
  21. 21.
    Palma JP, Rodriguez LE, Bontcheva-Diaz VD, Bouska JJ, Bukofzer G, Colon-Lopez M, Guan R, Jarvis K, Johnson EF, Klinghofer V, Liu X, Olson A, Saltarelli MJ, Shi Y, Stavropoulos JA, Zhu GD, Penning TD, Luo Y, Giranda VL, Rosenberg SH, Frost DJ, Donawho CK (2008) The PARP inhibitor, ABT-888 potentiates temozolomide: correlation with drug levels and reduction in PARP activity in vivo. Anticancer Res 28(5A):2625–2635Google Scholar
  22. 22.
    Brookes S, Gagrica S, Sanij E, Rowe J, Gregory FJ, Hara E, Peters G (2015) Evidence for a CDK4-dependent checkpoint in a conditional model of cellular senescence. Cell Cycle 14(8):1164–1173.  https://doi.org/10.1080/15384101.2015.1010866 CrossRefGoogle Scholar
  23. 23.
    Vermes I, Haanen C, Reutelingsperger C (2000) Flow cytometry of apoptotic cell death. J Immunol Methods 243(1–2):167–190CrossRefGoogle Scholar
  24. 24.
    He BC, Gao JL, Luo X, Luo J, Shen J, Wang L, Zhou Q, Wang YT, Luu HH, Haydon RC, Wang CZ, Du W, Yuan CS, He TC, Zhang BQ (2011) Ginsenoside Rg3 inhibits colorectal tumor growth through the down-regulation of Wnt/ss-catenin signaling. Int J Oncol 38(2):437–445.  https://doi.org/10.3892/ijo.2010.858 CrossRefGoogle Scholar
  25. 25.
    Xiao K, Luo J, Fowler WL, Li Y, Lee JS, Xing L, Cheng RH, Wang L, Lam KS (2009) A self-assembling nanoparticle for paclitaxel delivery in ovarian cancer. Biomaterials 30(30):6006–6016.  https://doi.org/10.1016/j.biomaterials.2009.07.015 CrossRefGoogle Scholar
  26. 26.
    Zhao E, Ilyas G, Cingolani F, Choi JH, Ravenelle F, Tanaka KE, Czaja MJ (2017) Pentamidine blocks hepatotoxic injury in mice. Hepatology 66(3):922–935.  https://doi.org/10.1002/hep.29244 CrossRefGoogle Scholar
  27. 27.
    Hammond WA, Swaika A, Mody K (2016) Pharmacologic resistance in colorectal cancer: a review. Ther Adv Med Oncol 8(1):57–84.  https://doi.org/10.1177/1758834015614530 CrossRefGoogle Scholar
  28. 28.
    Bradshaw-Pierce EL, Pitts TM, Kulikowski G, Selby H, Merz AL, Gustafson DL, Serkova NJ, Eckhardt SG, Weekes CD (2013) Utilization of quantitative in vivo pharmacology approaches to assess combination effects of everolimus and irinotecan in mouse xenograft models of colorectal cancer. PLoS One 8(3):e58089.  https://doi.org/10.1371/journal.pone.0058089 CrossRefGoogle Scholar
  29. 29.
    Tsukihara H, Nakagawa F, Sakamoto K, Ishida K, Tanaka N, Okabe H, Uchida J, Matsuo K, Takechi T (2015) Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, together with bevacizumab, cetuximab, or panitumumab on human colorectal cancer xenografts. Oncol Rep 33(5):2135–2142.  https://doi.org/10.3892/or.2015.3876 Google Scholar
  30. 30.
    Vormoor B, Curtin NJ (2014) Poly(ADP-ribose) polymerase inhibitors in Ewing sarcoma. Curr Opin Oncol 26(4):428–433.  https://doi.org/10.1097/CCO.0000000000000091 CrossRefGoogle Scholar
  31. 31.
    Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, Ji J, Takeda S, Pommier Y (2012) Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res 72(21):5588–5599.  https://doi.org/10.1158/0008-5472.CAN-12-2753 CrossRefGoogle Scholar
  32. 32.
    Noll DM, Mason TM, Miller PS (2006) Formation and repair of interstrand cross-links in DNA. Chem Rev 106(2):277–301.  https://doi.org/10.1021/cr040478b CrossRefGoogle Scholar
  33. 33.
    Nicolay NH, Ruhle A, Perez RL, Trinh T, Sisombath S, Weber KJ, Schmezer P, Ho AD, Debus J, Saffrich R, Huber PE (2016) Mesenchymal stem cells exhibit resistance to topoisomerase inhibition. Cancer Lett 374(1):75–84.  https://doi.org/10.1016/j.canlet.2016.02.007 CrossRefGoogle Scholar
  34. 34.
    Abdou I, Poirier GG, Hendzel MJ, Weinfeld M (2015) DNA ligase III acts as a DNA strand break sensor in the cellular orchestration of DNA strand break repair. Nucleic Acids Res 43(2):875–892.  https://doi.org/10.1093/nar/gku1307 CrossRefGoogle Scholar
  35. 35.
    Stewart E, Goshorn R, Bradley C, Griffiths LM, Benavente C, Twarog NR, Miller GM, Caufield W, Freeman BB 3rd, Bahrami A, Pappo A, Wu J, Loh A, Karlstrom A, Calabrese C, Gordon B, Tsurkan L, Hatfield MJ, Potter PM, Snyder SE, Thiagarajan S, Shirinifard A, Sablauer A, Shelat AA, Dyer MA (2014) Targeting the DNA repair pathway in Ewing sarcoma. Cell Rep 9(3):829–841.  https://doi.org/10.1016/j.celrep.2014.09.028 CrossRefGoogle Scholar
  36. 36.
    Cao TP, Kim JS, Woo MH, Choi JM, Jun Y, Lee KH, Lee SH (2016) Structural insight for substrate tolerance to 2-deoxyribose-5-phosphate aldolase from the pathogen Streptococcus suis. J Microbiol 54(4):311–321.  https://doi.org/10.1007/s12275-016-6029-4 CrossRefGoogle Scholar
  37. 37.
    Strumberg D, Pilon AA, Smith M, Hickey R, Malkas L, Pommier Y (2000) Conversion of topoisomerase I cleavage complexes on the leading strand of ribosomal DNA into 5′-phosphorylated DNA double-strand breaks by replication runoff. Mol Cell Biol 20(11):3977–3987CrossRefGoogle Scholar
  38. 38.
    Malanga M, Althaus FR (2004) Poly(ADP-ribose) reactivates stalled DNA topoisomerase I and induces DNA strand break resealing. J Biol Chem 279(7):5244–5248.  https://doi.org/10.1074/jbc.C300437200 CrossRefGoogle Scholar
  39. 39.
    Sugimura K, Takebayashi S, Taguchi H, Takeda S, Okumura K (2008) PARP-1 ensures regulation of replication fork progression by homologous recombination on damaged DNA. J Cell Biol 183(7):1203–1212.  https://doi.org/10.1083/jcb.200806068 CrossRefGoogle Scholar
  40. 40.
    Marechal A, Zou L (2013) DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb Perspect Biol 5(9).  https://doi.org/10.1101/cshperspect.a012716
  41. 41.
    Kaku Y, Tsuchiya A, Kanno T, Nishizaki T (2015) Irinotecan induces cell cycle arrest, but not apoptosis or necrosis, in Caco-2 and CW2 colorectal cancer cell lines. Pharmacology 95(3–4):154–159.  https://doi.org/10.1159/000381029 CrossRefGoogle Scholar
  42. 42.
    Williams AB, Schumacher B (2016) p53 in the DNA-damage-repair process. Cold Spring Harb Perspect Med 6(5).  https://doi.org/10.1101/cshperspect.a026070
  43. 43.
    Origanti S, Cai SR, Munir AZ, White LS, Piwnica-Worms H (2013) Synthetic lethality of Chk1 inhibition combined with p53 and/or p21 loss during a DNA damage response in normal and tumor cells. Oncogene 32(5):577–588.  https://doi.org/10.1038/onc.2012.84 CrossRefGoogle Scholar
  44. 44.
    Abd Elmageed ZY, Naura AS, Errami Y, Zerfaoui M (2012) The poly(ADP-ribose) polymerases (PARPs): new roles in intracellular transport. Cell Signal 24(1):1–8.  https://doi.org/10.1016/j.cellsig.2011.07.019 CrossRefGoogle Scholar
  45. 45.
    Davidson D, Wang Y, Aloyz R, Panasci L (2013) The PARP inhibitor ABT-888 synergizes irinotecan treatment of colon cancer cell lines. Investig New Drugs 31(2):461–468.  https://doi.org/10.1007/s10637-012-9886-7 CrossRefGoogle Scholar
  46. 46.
    Lieberman HB, Panigrahi SK, Hopkins KM, Wang L, Broustas CG (2017) p53 and RAD9, the DNA damage response, and regulation of transcription networks. Radiat Res 187(4):424–432.  https://doi.org/10.1667/RR003CC.1 CrossRefGoogle Scholar
  47. 47.
    Rosado MM, Bennici E, Novelli F, Pioli C (2013) Beyond DNA repair, the immunological role of PARP-1 and its siblings. Immunology 139(4):428–437.  https://doi.org/10.1111/imm.12099 CrossRefGoogle Scholar
  48. 48.
    Lee YC, Lee CH, Tsai HP, An HW, Lee CM, Wu JC, Chen CS, Huang SH, Hwang J, Cheng KT, Leiw PL, Chen CL, Lin CM (2015) Targeting of topoisomerase I for prognoses and therapeutics of camptothecin-resistant ovarian cancer. PLoS One 10(7):e0132579.  https://doi.org/10.1371/journal.pone.0132579 CrossRefGoogle Scholar
  49. 49.
    Huang K, Zhang J, O'Neill KL, Gurumurthy CB, Quadros RM, Tu Y, Luo X (2016) Cleavage by caspase 8 and mitochondrial membrane association activate the BH3-only protein bid during TRAIL-induced apoptosis. J Biol Chem 291(22):11843–11851.  https://doi.org/10.1074/jbc.M115.711051 CrossRefGoogle Scholar
  50. 50.
    McIlwain DR, Berger T, Mak TW (2015) Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol 7(4).  https://doi.org/10.1101/cshperspect.a026716
  51. 51.
    Mao D, Qiao L, Lu H, Feng Y (2016) B-cell translocation gene 3 overexpression inhibits proliferation and invasion of colorectal cancer SW480 cells via Wnt/beta-catenin signaling pathway. Neoplasma 63(5):705–716.  https://doi.org/10.4149/neo_2016_507 CrossRefGoogle Scholar
  52. 52.
    Melling N, Kowitz CM, Simon R, Bokemeyer C, Terracciano L, Sauter G, Izbicki JR, Marx AH (2016) High Ki67 expression is an independent good prognostic marker in colorectal cancer. J Clin Pathol 69(3):209–214.  https://doi.org/10.1136/jclinpath-2015-202985 CrossRefGoogle Scholar
  53. 53.
    Al-Ali H, Ding Y, Slepak T, Wu W, Sun Y, Martinez Y, Xu XM, Lemmon VP, Bixby JL (2017) The mTOR substrate S6 kinase 1 (S6K1) is a negative regulator of axon regeneration and a potential drug target for central nervous system injury. J Neurosci 37(30):7079–7095.  https://doi.org/10.1523/JNEUROSCI.0931-17.2017 CrossRefGoogle Scholar
  54. 54.
    Therkildsen C, Bergmann TK, Henrichsen-Schnack T, Ladelund S, Nilbert M (2014) The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: a systematic review and meta-analysis. Acta Oncol 53(7):852–864.  https://doi.org/10.3109/0284186X.2014.895036 CrossRefGoogle Scholar
  55. 55.
    Satelli A, Mitra A, Brownlee Z, Xia X, Bellister S, Overman MJ, Kopetz S, Ellis LM, Meng QH, Li S (2015) Epithelial-mesenchymal transitioned circulating tumor cells capture for detecting tumor progression. Clin Cancer Res 21(4):899–906.  https://doi.org/10.1158/1078-0432.CCR-14-0894 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Titto Augustine
    • 1
  • Radhashree Maitra
    • 2
  • Jinghang Zhang
    • 3
  • Jay Nayak
    • 2
  • Sanjay Goel
    • 1
    • 2
    Email author
  1. 1.Department of MedicineAlbert Einstein College of MedicineBronxUSA
  2. 2.Department of Medical OncologyMontefiore Medical CenterBronxUSA
  3. 3.Department of Microbiology & Immunology and Flow Cytometry Core FacilityAlbert Einstein College of MedicineBronxUSA

Personalised recommendations