Skip to main content

Advertisement

Log in

In the War Against Solid Tumors Arsenic Trioxide Need Partners

  • Invited Reviews
  • Published:
Journal of Gastrointestinal Cancer Aims and scope Submit manuscript

Abstract

In the past decade, the therapeutic potential of arsenic trioxide (ATO) in the treatment of acute promyelocytic leukemia (APL) was recognized. This encouraged other investigators to test the efficacy of ATO in the management of other hematological and solid tumor malignancies. Notably, as a single agent, arsenic trioxide did not benefit patients diagnosed with solid tumors. However, when it was combined with other agents, treatment benefit emerged. In this article, we have summarized the outcome of clinical trials that used arsenic trioxide as a single agent as well as in combination settings in patients diagnosed with solid tumors. We have also reviewed possible additional mechanisms by which ATO may be useful as a chemosensitizer in combination therapy. We hope that our review will encourage clinical investigators to rationally combine ATO with additional chemotherapeutic agents in treating patients diagnosed with solid tumors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Zhu J, Chen Z, Lallemand-Breitenbach V, de The H. How acute promyelocytic leukaemia revived arsenic. Nat Rev Cancer. 2002;2:705–13.

    Article  CAS  PubMed  Google Scholar 

  2. Emadi A, Gore SD. Arsenic trioxide—an old drug rediscovered. Blood Rev. 2010;24:191–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Zhu J, Koken MH, Quignon F, Chelbi-Alix MK, Degos L, Wang ZY, et al. Arsenic-induced PML targeting onto nuclear bodies: implications for the treatment of acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 1997;94:3978–83.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Salomoni P, Pandolfi PP. The role of PML in tumor suppression. Cell. 2002;108:165–70.

    Article  CAS  PubMed  Google Scholar 

  5. Chen GQ, Zhu J, Shi XG, Ni JH, Zhong HJ, Si GY, et al. In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia: As2O3 induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML-RAR alpha/PML proteins. Blood. 1996;88:1052–61.

    CAS  PubMed  Google Scholar 

  6. Chen GQ, Shi XG, Tang W, Xiong SM, Zhu J, Cai X, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells. Blood. 1997;89:3345–53.

    CAS  PubMed  Google Scholar 

  7. Soignet SL, Maslak P, Wang ZG, Jhanwar S, Calleja E, Dardashti LJ, et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med. 1998;339:1341–8.

    Article  CAS  PubMed  Google Scholar 

  8. Beer TM, Tangen CM, Nichols CR, Margolin KA, Dreicer R, Stephenson WT, et al. Southwest Oncology Group phase II study of arsenic trioxide in patients with refractory germ cell malignancies. Cancer. 2006;106:2624–9.

    Article  CAS  PubMed  Google Scholar 

  9. Vuky J, Yu R, Schwartz L, Motzer RJ. Phase II trial of arsenic trioxide in patients with metastatic renal cell carcinoma. Invest New Drugs. 2002;20:327–30.

    Article  CAS  PubMed  Google Scholar 

  10. Lin CC, Hsu C, Hsu CH, Hsu WL, Cheng AL, Yang CH. Arsenic trioxide in patients with hepatocellular carcinoma: a phase II trial. Invest New Drugs. 2007;25:77–84.

    Article  CAS  PubMed  Google Scholar 

  11. Lin CC, Pu YS, Hsu CH, Keng HY, Cheng AL, Yang CH. Acute encephalopathy following arsenic trioxide for metastatic urothelial carcinoma. Urol Oncol. 2008;26:659–61.

    Article  CAS  PubMed  Google Scholar 

  12. Kindler HL, Aklilu M, Nattam S, Vokes EE. Arsenic trioxide in patients with adenocarcinoma of the pancreas refractory to gemcitabine: a phase II trial of the University of Chicago Phase II Consortium. Am J Clin Oncol. 2008;31:553–6.

    Article  CAS  PubMed  Google Scholar 

  13. Lai YL, Chang HH, Huang MJ, Chang KH, Su WH, Chen HW, et al. Combined effect of topical arsenic trioxide and radiation therapy on skin-infiltrating lesions of breast cancer—a pilot study. Anticancer Drugs. 2003;14:825–8.

    Article  CAS  PubMed  Google Scholar 

  14. Huilgol NG. A phase I study to study arsenic trioxide with radiation and hyperthermia in advanced head and neck cancer. Int J Hyperthermia. 2006;22:391–7.

    Article  CAS  PubMed  Google Scholar 

  15. Grimm SA, Marymont M, Chandler JP, Muro K, Newman SB, Levy RM, et al. Phase I study of arsenic trioxide and temozolomide in combination with radiation therapy in patients with malignant gliomas. J Neurooncol. 2012;110:237–43.

    Article  CAS  PubMed  Google Scholar 

  16. Niki E. Action of ascorbic acid as a scavenger of active and stable oxygen radicals. Am J Clin Nutr. 1991;54:1119S–24S.

    CAS  PubMed  Google Scholar 

  17. Danenberg PV. Thymidylate synthetase—a target enzyme in cancer chemotherapy. Biochim Biophys Acta. 1977;473:73–92.

    CAS  PubMed  Google Scholar 

  18. Subbarayan PR, Lima M, Ardalan B. Arsenic trioxide/ascorbic acid therapy in patients with refractory metastatic colorectal carcinoma: a clinical experience. Acta Oncol. 2007;46:557–61.

    Article  CAS  PubMed  Google Scholar 

  19. Johnston PG, Lenz HJ, Leichman CG, Danenberg KD, Allegra CJ, Danenberg PV, et al. Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res. 1995;55:1407–12.

    CAS  PubMed  Google Scholar 

  20. Bathe OF, Franceschi D, Livingstone AS, Moffat FL, Tian E, Ardalan B. Increased thymidylate synthase gene expression in liver metastases from colorectal carcinoma: implications for chemotherapeutic options and survival. Cancer J Sci Am. 1999;5:34–40.

    CAS  PubMed  Google Scholar 

  21. Subbarayan PR, Lee K, Ardalan B. Arsenic trioxide suppresses thymidylate synthase in 5-FU-resistant colorectal cancer cell line HT29 in vitro re-sensitizing cells to 5-FU. Anticancer Res. 2010;30:1157–62.

    CAS  PubMed  Google Scholar 

  22. Subbarayan PR, Sarkar M, Nelson G, Benitez E, Singhal S, Ardalan B. Chronic exposure of colorectal cancer cells in culture to fluoropyrimidine analogs induces thymidylate synthase and suppresses p53. A molecular explanation for the mechanism of 5-FU resistance. Anticancer Res. 2010;30:1149–56.

    CAS  PubMed  Google Scholar 

  23. Ardalan B, Subbarayan PR, Ramos Y, Gonzalez M, Fernandez A, Mezentsev D, et al. A phase I study of 5-fluorouracil/leucovorin and arsenic trioxide for patients with refractory/relapsed colorectal carcinoma. Clin Cancer Res. 2010;16:3019–27.

    Article  CAS  PubMed  Google Scholar 

  24. Podolsky L, Oh M, Subbarayan PR, Francheschi D, Livingstone A, Ardalan B. 5-Fluorouracil/leucovorin and arsenic trioxide for patients with refractory/relapsed colorectal carcinoma: a clinical experience. Acta Oncol. 2011;50:602–5.

    Article  CAS  PubMed  Google Scholar 

  25. Altucci L, Gronemeyer H. The promise of retinoids to fight against cancer. Nat Rev Cancer. 2001;1:181–93.

    Article  CAS  PubMed  Google Scholar 

  26. Kinzler KW, Vogelstein B. The GLI gene encodes a nuclear protein which binds specific sequences in the human genome. Mol Cell Biol. 1990;10:634–42.

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Altaba A, Sanchez P, Dahmane N. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer. 2002;2:361–72.

    Article  Google Scholar 

  28. Beauchamp EM, Uren A. A new era for an ancient drug: arsenic trioxide and hedgehog signaling. Vitam Horm. 2012;88:333–54.

    Article  CAS  PubMed  Google Scholar 

  29. Yun JI, Kim HR, Park H, Kim SK, Lee J. Small molecule inhibitors of the hedgehog signaling pathway for the treatment of cancer. Arch Pharm Res. 2012;35:1317–33.

    Article  CAS  PubMed  Google Scholar 

  30. Metcalfe C, de Sauvage FJ. Hedgehog fights back: mechanisms of acquired resistance against Smoothened antagonists. Cancer Res. 2011;71:5057–61.

    Article  CAS  PubMed  Google Scholar 

  31. Robbins DJ, Fei DL, Riobo NA. The Hedgehog signal transduction network. Sci Signal 2012; 5:re6.

  32. Kim J, Lee JJ, Kim J, Gardner D, Beachy PA. Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector. Proc Natl Acad Sci U S A. 2010;107:13432–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Shi T, Mazumdar T, Devecchio J, Duan ZH, Agyeman A, Aziz M et al. cDNA microarray gene expression profiling of hedgehog signaling pathway inhibition in human colon cancer cells. PLoS One 2010; 5.

  34. Oliver TG, Grasfeder LL, Carroll AL, Kaiser C, Gillingham CL, Lin SM, et al. Transcriptional profiling of the Sonic hedgehog response: a critical role for N-myc in proliferation of neuronal precursors. Proc Natl Acad Sci U S A. 2003;100:7331–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Rangwala F, Williams KP, Smith GR, Thomas Z, Allensworth JL, Lyerly HK, et al. Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines. BMC Cancer. 2012;12:402.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Ardalan B, Luis R, Jaime M, Franceschi D. Biomodulation of fluorouracil in colorectal cancer. Cancer Invest. 1998;16:237–51.

    Article  CAS  PubMed  Google Scholar 

  37. Chu E, Koeller DM, Casey JL, Drake JC, Chabner BA, Elwood PC, et al. Autoregulation of human thymidylate synthase messenger RNA translation by thymidylate synthase. Proc Natl Acad Sci U S A. 1991;88:8977–81.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Chu E, Allegra CJ. Mechanisms of clinical resistance to 5-fluorouracil chemotherapy. Cancer Treat Res. 1996;87:175–95.

    Article  CAS  PubMed  Google Scholar 

  39. Kaneda S, Nalbantoglu J, Takeishi K, Shimizu K, Gotoh O, Seno T, et al. Structural and functional analysis of the human thymidylate synthase gene. J Biol Chem. 1990;265:20277–84.

    CAS  PubMed  Google Scholar 

  40. Chow SK, Chan JY, Fung KP. Inhibition of cell proliferation and the action mechanisms of arsenic trioxide (As2O3) on human breast cancer cells. J Cell Biochem. 2004;93:173–87.

    Article  CAS  PubMed  Google Scholar 

  41. Ye J, Li A, Liu Q, Wang X, Zhou J. Inhibition of mitogen-activated protein kinase kinase enhances apoptosis induced by arsenic trioxide in human breast cancer MCF-7 cells. Clin Exp Pharmacol Physiol. 2005;32:1042–8.

    Article  CAS  PubMed  Google Scholar 

  42. Wang Y, Zhang Y, Yang L, Cai B, Li J, Zhou Y, et al. Arsenic trioxide induces the apoptosis of human breast cancer MCF-7 cells through activation of caspase-3 and inhibition of HERG channels. Exp Ther Med. 2011;2:481–6.

    PubMed Central  PubMed  Google Scholar 

  43. Kang YH, Yi MJ, Kim MJ, Park MT, Bae S, Kang CM, et al. Caspase-independent cell death by arsenic trioxide in human cervical cancer cells: reactive oxygen species-mediated poly(ADP-ribose) polymerase-1 activation signals apoptosis-inducing factor release from mitochondria. Cancer Res. 2004;64:8960–7.

    Article  CAS  PubMed  Google Scholar 

  44. Kuo CC, Liu TW, Chen LT, Shiah HS, Wu CM, Cheng YT, et al. Combination of arsenic trioxide and BCNU synergistically triggers redox-mediated autophagic cell death in human solid tumors. Free Radic Biol Med. 2011;51:2195–209.

    Article  CAS  PubMed  Google Scholar 

  45. Hallahan DE, Spriggs DR, Beckett MA, Kufe DW, Weichselbaum RR. Increased tumor necrosis factor alpha mRNA after cellular exposure to ionizing radiation. Proc Natl Acad Sci U S A. 1989;86:10104–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Lew YS, Kolozsvary A, Brown SL, Kim JH. Synergistic interaction with arsenic trioxide and fractionated radiation in locally advanced murine tumor. Cancer Res. 2002;62:4202–5.

    CAS  PubMed  Google Scholar 

  47. Yin JQ, Zhao RC, Morris KV. Profiling microRNA expression with microarrays. Trends Biotechnol. 2008;26:70–6.

    Article  CAS  PubMed  Google Scholar 

  48. Liang H, Li X, Wang L, Yu S, Xu Z, Gu Y, et al. MicroRNAs contribute to promyelocyte apoptosis in As2O3-treated APL cells. Cell Physiol Biochem. 2013;32:1818–29.

    Article  CAS  PubMed  Google Scholar 

  49. Gu J, Zhu X, Li Y, Dong D, Yao J, Lin C, et al. miRNA-21 regulates arsenic-induced anti-leukemia activity in myelogenous cell lines. Med Oncol. 2011;28:211–8.

    Article  CAS  PubMed  Google Scholar 

  50. Li Y, Zhu X, Gu J, Dong D, Yao J, Lin C, et al. Anti-miR-21 oligonucleotide sensitizes leukemic K562 cells to arsenic trioxide by inducing apoptosis. Cancer Sci. 2010;101:948–54.

    Article  CAS  PubMed  Google Scholar 

  51. Liu L, Chen R, Huang S, Wu Y, Li G, Zhang B, et al. miR-153 sensitized the K562 cells to As2O3-induced apoptosis. Med Oncol. 2012;29:243–7.

    Article  CAS  PubMed  Google Scholar 

  52. Meng XZ, Zheng TS, Chen X, Wang JB, Zhang WH, Pan SH, et al. microRNA expression alteration after arsenic trioxide treatment in HepG-2 cells. J Gastroenterol Hepatol. 2011;26:186–93.

    Article  CAS  PubMed  Google Scholar 

  53. Cao Y, Yu SL, Wang Y, Guo GY, Ding Q, An RH. MicroRNA-dependent regulation of PTEN after arsenic trioxide treatment in bladder cancer cell line T24. Tumour Biol. 2011;32:179–88.

    Article  CAS  PubMed  Google Scholar 

  54. Shan H, Zhang Y, Cai B, Chen X, Fan Y, Yang L, et al. Upregulation of microRNA-1 and microRNA-133 contributes to arsenic-induced cardiac electrical remodeling. Int J Cardiol. 2013;167:2798–805.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by NCI 1R21CA117116-01A2, Sheibar Foundation, and McDonald Research foundation grants to BA. Additional support was provided by the American Cancer Society Institutional Research Grant (IRG no. 98-277-07), Interdisciplinary Research Development Initiative (IRDI no. 102504) award, and University of Miami Clinical and Translational Science Institute (CTSI) Pilot Research Grant (CTSI-2013-P03) to PRS. The Pilot and Collaborative Translational and Clinical Studies component is supported by Grant No. 1UL1TR000460, the University of Miami CTSI, from the National Center for Advancing Translational Sciences and the National Institute on Minority Health and Health Disparities. In our effort to keep this article concise and focused, we regret not to have included all citations.

Conflict of interest

We declare no competing interests.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bach Ardalan.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Subbarayan, P.R., Ardalan, B. In the War Against Solid Tumors Arsenic Trioxide Need Partners. J Gastrointest Canc 45, 363–371 (2014). https://doi.org/10.1007/s12029-014-9617-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12029-014-9617-8

Keywords

Navigation