Leukemia & Lymphoma
ISSN: 1042-8194 (Print) 1029-2403 (Online) Journal homepage: http://www.tandfonline.com/loi/ilal20
Synergism between arsenic trioxide and aclacinomycin in acute myeloid leukemia Dennis J. Goussetis & Leonidas C. Platanias To cite this article: Dennis J. Goussetis & Leonidas C. Platanias (2015): Synergism between arsenic trioxide and aclacinomycin in acute myeloid leukemia, Leukemia & Lymphoma To link to this article: http://dx.doi.org/10.3109/10428194.2015.1044450
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Accepted author version posted online: 05 May 2015. Published online: 18 Jun 2015. Submit your article to this journal
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ilal20 Download by: [Chinese University of Hong Kong]
Date: 19 November 2015, At: 00:04
Leukemia & Lymphoma, 2015; Early Online: 1–2 © 2015 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2015.1044450
COMMENTARY
Synergism between arsenic trioxide and aclacinomycin in acute myeloid leukemia Dennis J. Goussetis1 & Leonidas C. Platanias2 1Incyte Corporation, Wilmington, Delaware and 2Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-
Downloaded by [Chinese University of Hong Kong] at 00:04 19 November 2015
Oncology, Northwestern University Medical School, Chicago, IL, USA Acute myeloid leukemia (AML) is a genetically heterogeneous disease with aggressive treatment options comprised of different treatment phases depending on disease stage [1], such as remission induction therapy aimed to eliminate actively proliferating tumor cells and post-remission therapy aimed to prevent relapse. Despite advances in the understanding of the disease and treatment options, the expected remission rate is inversely related to age, particularly for patients over the age of 60 [2]. Therefore, there is increased interest in the investigation of novel combination therapies that could result in better outcomes. Arsenic trioxide (ATO) is a potent pro-differentiating and pro-apoptotic drug used in the treatment of acute promyelocytic leukemia (APL) cells [3]. It is usually given in combination with all-trans-retinoic acid (ATRA), either during induction therapy or in the course of the consolidation phase [4]. The limitation in the use of ATO as an anti-cancer agent is the multitude of toxic side-effects, such as gastrointestinal and cardiac toxicity, particularly at higher doses and/or upon long-term exposure. This agent has been shown to affect a plethora of intercellular signal pathways, including being a potent inducer of apoptosis by elevating intracellular H2O2 or increasing expression of BAX as two of the possible mechanism of actions [5]. Additionally, combination of ATO with other compounds enhances clinical therapeutic outcomes [6]. Aclacinomyin (ACM) is an anti-tumor antibiotic with cytotoxic effects due to its DNA intercalating activity and topoisomerase I and II enzyme inhibition [7]. In solid tumors, ACM was found to act as a radiosensitizer [8]. In hematopoietic malignancies, ACM induced erythroid differentiation of the erythroleukemia CML cell line K562 [9]. In a recent clinical trial on refractory AML patients, a drug combination including ACM achieved higher levels of complete response and improved overall survival with acceptable cytotoxic effects [10]. In this issue of Leukemia and Lymphoma, Ye et al. [11] identify a synergistic effect by the combination of low dose Arsenic Trioxide with the antibiotic aclacinomycin in human
models of AML. They show that a combination of Arsenic trioxide with aclacinomycin leads to increased apoptosis compared to drug alone and their effects are synergistic. This is achieved even at low ATO (0.4 mM) and ACM (10 nM) concentrations with a combination index (CI) 0.5 in acute myeloid leukemia cell lines (KG-1a and HL-60). The effect was also evidenced by the decrease of pro-apoptotic markers Bcl-2, c-IAP and XIAP and increase of the pro-apoptotic proteins caspase-3 and SMAC. Similarly G0/G1 arrest and S phase induction was observed, adding cell cycle arrest as an additional mechanism of suppression exerted by both drugs. Interestingly, compared to proliferative AML cells, minimal apoptosis was recorded in peripheral blood mononuclear cells (PBMNCs) with the combination treatments. For the first time, Ye et al. [11] show synergistic anti-cancer events upon combination of ATO with aclacinomycin. Combination therapy could prove useful in both treatment phases of AML. The enhanced apoptosis observed by combination of aclacinomycin with ATO is potentially applicable to the induction phase of treatment, while the involvement of both drugs in differentiation of AML cells could be applied to prevent relapse by differentiating the remaining stem cells. As previous studies have shown that both drugs separately induce differentiation of AML cells [12,13], the synergy reported by Ye et al. [11] establishes the foundation of further research in the combinational effect of ATO and aclacinomycin, not only in the pro-apoptotic effects, but also any potential differentiation of AML cells, particularly in the case of ATRA-resistance development. Clearly more experiments and data are needed to better understand the mechanism of action of either drug alone and in combination with each other. The inter-play of cell death and cell cycle pathways could be further explored, since the authors suggested AMC-induced apoptosis may be regulated independently of apoptosis-related signals and more associated directly with the cell cycle arrest process. Furthermore, other cell death pathways could be investigated since ATO has been shown to induce autophagy in leukemic cells; however, minimal studies have examined the role of AMC in
Correspondence: Dennis J. Goussetis, Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School, Chicago, IL, USA. E-mail: [email protected] This commentary accompanies an article to be published in Leukemia and Lymphoma. Please refer to the table of contents of the print issue in which this commentary appears.
1 ILAL_A_1044450.indd 1
6/3/2015 5:13:55 PM
2 D. J. Goussetis & L. C. Platanias this type-II program cell death pathway. Using the combinational treatments in either primary AML cells or in an animal model would also add important information in the clinical implications for the combinations of these two drugs. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal
Downloaded by [Chinese University of Hong Kong] at 00:04 19 November 2015
References [1] Conway O’Brien E, Prideaux S, Chevassut T. The epigenetic landscape of acute myeloid leukemia. Adv Hematol 2014;2014:103175. [2] Rowe JM, Tallman MS. How I treat acute myeloid leukemia. Blood 2010;116:3147–3156. [3] Platanias LC. Biological responses to arsenic compounds. J Biol Chem 2009;284:18583–18587. [4] Breccia M, Cicconi L, Lo-Coco F. ATRA ATO: has a new standard of care been established in low-risk acute promyelocytic leukaemia? Curr Opin Hematol 2014;21:95–101. [5] Miller WH, Jr, Schipper HM, Lee JS, et al. Mechanisms of action of arsenic trioxide. Cancer Res 2002;62:3893–3903.
ILAL_A_1044450.indd 2
[6] Takahashi S. Combination therapy with arsenic trioxide for hematological malignancies. Anti-Cancer Agents Med Chem 2010; 10:504–510. [7] Warrell RP, Jr. Aclacinomycin A: clinical development of a novel anthracycline antibiotic in the haematological cancers. Drugs Under Exp Clin Res 1986;12:275–282. [8] Bennett DC, Charest J, Sebolt K, et al. High-throughput screening identifies aclacinomycin as a radiosensitizer of EGFR-mutant nonsmall cell lung cancer. Transl Oncol 2013;6:382–391. [9] Nyoung MN, Trentesaux C, Aries A, et al. Effect of aclacinomycindoxorubicin association on differentiation and growth of human erythroleukemic K562 cells. Anticancer Res 1994;14:1203–1208. [10] Song LX, Xu L, Li X, et al. Clinical outcome of treatment with a combined regimen of decitabine and aclacinomycin/cytarabine for patients with refractory acute myeloid leukemia. Ann Hematol 2012;91:1879–1886. [11] Ye Y, Xu X, Zhang M, et al. Low-dose Arsenic trioxide combined with aclacinomycin A synergistically enhance the cytotoxic effect on human acute myelogenous leukemia cell line by induction of apoptosis. Leuk lymphoma 2015; :1–26. [12] Sato S, Sakashita A, Ishiyama T, et al. Possible differentiation treatment with aclacinomycin A in acute myelomonocytic leukemia refractory to conventional chemotherapy. Anticancer Res 1992;12: 371–376. [13] Hu XM, Yuan B, Tanaka S, et al. Arsenic disulfide-triggered apoptosis and erythroid differentiation in myelodysplastic syndrome and acute myeloid leukemia cell lines. Hematology 2014;19:352–360.
6/3/2015 5:13:55 PM
ISSN: 1042-8194 (Print) 1029-2403 (Online) Journal homepage: http://www.tandfonline.com/loi/ilal20
Synergism between arsenic trioxide and aclacinomycin in acute myeloid leukemia Dennis J. Goussetis & Leonidas C. Platanias To cite this article: Dennis J. Goussetis & Leonidas C. Platanias (2015): Synergism between arsenic trioxide and aclacinomycin in acute myeloid leukemia, Leukemia & Lymphoma To link to this article: http://dx.doi.org/10.3109/10428194.2015.1044450
View supplementary material
Accepted author version posted online: 05 May 2015. Published online: 18 Jun 2015. Submit your article to this journal
Article views: 23
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ilal20 Download by: [Chinese University of Hong Kong]
Date: 19 November 2015, At: 00:04
Leukemia & Lymphoma, 2015; Early Online: 1–2 © 2015 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2015.1044450
COMMENTARY
Synergism between arsenic trioxide and aclacinomycin in acute myeloid leukemia Dennis J. Goussetis1 & Leonidas C. Platanias2 1Incyte Corporation, Wilmington, Delaware and 2Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-
Downloaded by [Chinese University of Hong Kong] at 00:04 19 November 2015
Oncology, Northwestern University Medical School, Chicago, IL, USA Acute myeloid leukemia (AML) is a genetically heterogeneous disease with aggressive treatment options comprised of different treatment phases depending on disease stage [1], such as remission induction therapy aimed to eliminate actively proliferating tumor cells and post-remission therapy aimed to prevent relapse. Despite advances in the understanding of the disease and treatment options, the expected remission rate is inversely related to age, particularly for patients over the age of 60 [2]. Therefore, there is increased interest in the investigation of novel combination therapies that could result in better outcomes. Arsenic trioxide (ATO) is a potent pro-differentiating and pro-apoptotic drug used in the treatment of acute promyelocytic leukemia (APL) cells [3]. It is usually given in combination with all-trans-retinoic acid (ATRA), either during induction therapy or in the course of the consolidation phase [4]. The limitation in the use of ATO as an anti-cancer agent is the multitude of toxic side-effects, such as gastrointestinal and cardiac toxicity, particularly at higher doses and/or upon long-term exposure. This agent has been shown to affect a plethora of intercellular signal pathways, including being a potent inducer of apoptosis by elevating intracellular H2O2 or increasing expression of BAX as two of the possible mechanism of actions [5]. Additionally, combination of ATO with other compounds enhances clinical therapeutic outcomes [6]. Aclacinomyin (ACM) is an anti-tumor antibiotic with cytotoxic effects due to its DNA intercalating activity and topoisomerase I and II enzyme inhibition [7]. In solid tumors, ACM was found to act as a radiosensitizer [8]. In hematopoietic malignancies, ACM induced erythroid differentiation of the erythroleukemia CML cell line K562 [9]. In a recent clinical trial on refractory AML patients, a drug combination including ACM achieved higher levels of complete response and improved overall survival with acceptable cytotoxic effects [10]. In this issue of Leukemia and Lymphoma, Ye et al. [11] identify a synergistic effect by the combination of low dose Arsenic Trioxide with the antibiotic aclacinomycin in human
models of AML. They show that a combination of Arsenic trioxide with aclacinomycin leads to increased apoptosis compared to drug alone and their effects are synergistic. This is achieved even at low ATO (0.4 mM) and ACM (10 nM) concentrations with a combination index (CI) 0.5 in acute myeloid leukemia cell lines (KG-1a and HL-60). The effect was also evidenced by the decrease of pro-apoptotic markers Bcl-2, c-IAP and XIAP and increase of the pro-apoptotic proteins caspase-3 and SMAC. Similarly G0/G1 arrest and S phase induction was observed, adding cell cycle arrest as an additional mechanism of suppression exerted by both drugs. Interestingly, compared to proliferative AML cells, minimal apoptosis was recorded in peripheral blood mononuclear cells (PBMNCs) with the combination treatments. For the first time, Ye et al. [11] show synergistic anti-cancer events upon combination of ATO with aclacinomycin. Combination therapy could prove useful in both treatment phases of AML. The enhanced apoptosis observed by combination of aclacinomycin with ATO is potentially applicable to the induction phase of treatment, while the involvement of both drugs in differentiation of AML cells could be applied to prevent relapse by differentiating the remaining stem cells. As previous studies have shown that both drugs separately induce differentiation of AML cells [12,13], the synergy reported by Ye et al. [11] establishes the foundation of further research in the combinational effect of ATO and aclacinomycin, not only in the pro-apoptotic effects, but also any potential differentiation of AML cells, particularly in the case of ATRA-resistance development. Clearly more experiments and data are needed to better understand the mechanism of action of either drug alone and in combination with each other. The inter-play of cell death and cell cycle pathways could be further explored, since the authors suggested AMC-induced apoptosis may be regulated independently of apoptosis-related signals and more associated directly with the cell cycle arrest process. Furthermore, other cell death pathways could be investigated since ATO has been shown to induce autophagy in leukemic cells; however, minimal studies have examined the role of AMC in
Correspondence: Dennis J. Goussetis, Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School, Chicago, IL, USA. E-mail: [email protected] This commentary accompanies an article to be published in Leukemia and Lymphoma. Please refer to the table of contents of the print issue in which this commentary appears.
1 ILAL_A_1044450.indd 1
6/3/2015 5:13:55 PM
2 D. J. Goussetis & L. C. Platanias this type-II program cell death pathway. Using the combinational treatments in either primary AML cells or in an animal model would also add important information in the clinical implications for the combinations of these two drugs. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal
Downloaded by [Chinese University of Hong Kong] at 00:04 19 November 2015
References [1] Conway O’Brien E, Prideaux S, Chevassut T. The epigenetic landscape of acute myeloid leukemia. Adv Hematol 2014;2014:103175. [2] Rowe JM, Tallman MS. How I treat acute myeloid leukemia. Blood 2010;116:3147–3156. [3] Platanias LC. Biological responses to arsenic compounds. J Biol Chem 2009;284:18583–18587. [4] Breccia M, Cicconi L, Lo-Coco F. ATRA ATO: has a new standard of care been established in low-risk acute promyelocytic leukaemia? Curr Opin Hematol 2014;21:95–101. [5] Miller WH, Jr, Schipper HM, Lee JS, et al. Mechanisms of action of arsenic trioxide. Cancer Res 2002;62:3893–3903.
ILAL_A_1044450.indd 2
[6] Takahashi S. Combination therapy with arsenic trioxide for hematological malignancies. Anti-Cancer Agents Med Chem 2010; 10:504–510. [7] Warrell RP, Jr. Aclacinomycin A: clinical development of a novel anthracycline antibiotic in the haematological cancers. Drugs Under Exp Clin Res 1986;12:275–282. [8] Bennett DC, Charest J, Sebolt K, et al. High-throughput screening identifies aclacinomycin as a radiosensitizer of EGFR-mutant nonsmall cell lung cancer. Transl Oncol 2013;6:382–391. [9] Nyoung MN, Trentesaux C, Aries A, et al. Effect of aclacinomycindoxorubicin association on differentiation and growth of human erythroleukemic K562 cells. Anticancer Res 1994;14:1203–1208. [10] Song LX, Xu L, Li X, et al. Clinical outcome of treatment with a combined regimen of decitabine and aclacinomycin/cytarabine for patients with refractory acute myeloid leukemia. Ann Hematol 2012;91:1879–1886. [11] Ye Y, Xu X, Zhang M, et al. Low-dose Arsenic trioxide combined with aclacinomycin A synergistically enhance the cytotoxic effect on human acute myelogenous leukemia cell line by induction of apoptosis. Leuk lymphoma 2015; :1–26. [12] Sato S, Sakashita A, Ishiyama T, et al. Possible differentiation treatment with aclacinomycin A in acute myelomonocytic leukemia refractory to conventional chemotherapy. Anticancer Res 1992;12: 371–376. [13] Hu XM, Yuan B, Tanaka S, et al. Arsenic disulfide-triggered apoptosis and erythroid differentiation in myelodysplastic syndrome and acute myeloid leukemia cell lines. Hematology 2014;19:352–360.
6/3/2015 5:13:55 PM
