Journal of Gastrointestinal Cancer

, Volume 45, Issue 3, pp 363–371 | Cite as

In the War Against Solid Tumors Arsenic Trioxide Need Partners

  • Pochi R. Subbarayan
  • Bach ArdalanEmail author
Invited Reviews


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.


Thymidylate synthase miRNA Hedgehog signaling Combination therapy ATO Solid tumor malignancies Arsenic-containing compounds 



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.


  1. 1.
    Zhu J, Chen Z, Lallemand-Breitenbach V, de The H. How acute promyelocytic leukaemia revived arsenic. Nat Rev Cancer. 2002;2:705–13.PubMedCrossRefGoogle Scholar
  2. 2.
    Emadi A, Gore SD. Arsenic trioxide—an old drug rediscovered. Blood Rev. 2010;24:191–9.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Salomoni P, Pandolfi PP. The role of PML in tumor suppression. Cell. 2002;108:165–70.PubMedCrossRefGoogle Scholar
  5. 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.PubMedGoogle Scholar
  6. 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.PubMedGoogle Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. 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.PubMedCrossRefGoogle Scholar
  9. 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.PubMedCrossRefGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 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.PubMedCrossRefGoogle Scholar
  16. 16.
    Niki E. Action of ascorbic acid as a scavenger of active and stable oxygen radicals. Am J Clin Nutr. 1991;54:1119S–24S.PubMedGoogle Scholar
  17. 17.
    Danenberg PV. Thymidylate synthetase—a target enzyme in cancer chemotherapy. Biochim Biophys Acta. 1977;473:73–92.PubMedGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 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.PubMedGoogle Scholar
  20. 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.PubMedGoogle Scholar
  21. 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.PubMedGoogle Scholar
  22. 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.PubMedGoogle Scholar
  23. 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.PubMedCrossRefGoogle Scholar
  24. 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.PubMedCrossRefGoogle Scholar
  25. 25.
    Altucci L, Gronemeyer H. The promise of retinoids to fight against cancer. Nat Rev Cancer. 2001;1:181–93.PubMedCrossRefGoogle Scholar
  26. 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.PubMedCentralPubMedGoogle Scholar
  27. 27.
    Altaba A, Sanchez P, Dahmane N. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer. 2002;2:361–72.CrossRefGoogle Scholar
  28. 28.
    Beauchamp EM, Uren A. A new era for an ancient drug: arsenic trioxide and hedgehog signaling. Vitam Horm. 2012;88:333–54.PubMedCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 30.
    Metcalfe C, de Sauvage FJ. Hedgehog fights back: mechanisms of acquired resistance against Smoothened antagonists. Cancer Res. 2011;71:5057–61.PubMedCrossRefGoogle Scholar
  31. 31.
    Robbins DJ, Fei DL, Riobo NA. The Hedgehog signal transduction network. Sci Signal 2012; 5:re6.Google Scholar
  32. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 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.Google Scholar
  34. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Ardalan B, Luis R, Jaime M, Franceschi D. Biomodulation of fluorouracil in colorectal cancer. Cancer Invest. 1998;16:237–51.PubMedCrossRefGoogle Scholar
  37. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Chu E, Allegra CJ. Mechanisms of clinical resistance to 5-fluorouracil chemotherapy. Cancer Treat Res. 1996;87:175–95.PubMedCrossRefGoogle Scholar
  39. 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.PubMedGoogle Scholar
  40. 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.PubMedCrossRefGoogle Scholar
  41. 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.PubMedCrossRefGoogle Scholar
  42. 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.PubMedCentralPubMedGoogle Scholar
  43. 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.PubMedCrossRefGoogle Scholar
  44. 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.PubMedCrossRefGoogle Scholar
  45. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 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.PubMedGoogle Scholar
  47. 47.
    Yin JQ, Zhao RC, Morris KV. Profiling microRNA expression with microarrays. Trends Biotechnol. 2008;26:70–6.PubMedCrossRefGoogle Scholar
  48. 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.PubMedCrossRefGoogle Scholar
  49. 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.PubMedCrossRefGoogle Scholar
  50. 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.PubMedCrossRefGoogle Scholar
  51. 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.PubMedCrossRefGoogle Scholar
  52. 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.PubMedCrossRefGoogle Scholar
  53. 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.PubMedCrossRefGoogle Scholar
  54. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of MedicineUniversity of Miami Miller School of MedicineMiamiUSA

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