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CDDO-Im, an antitumor molecule that also improves platetet production
Leukemia Research 35 (2011) 427–428
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Guest editorial
CDDO-Im, an antitumor molecule that also improves platetet production
Keywords: Triterpenoids CDDO-Im Megakaryocytic differentiation ROS
In their study Petronelli et al. [1] describe for the first time that CDDO-Im (cyano-3,12-dioxooleana-1,9 (11)-dien-28-imidazolide), a synthetic derivative of oleanolic acid, induces megakaryocytic differentiation of normal hematopoietic progenitor cells (HPCs). They propose that this drug could be eventually used to increase platelets production in patients with such deficiency. Triterpenoids are a large family of naturally occurring organic molecules (more than 20,000) with a variety of pharmacologic properties. Some of them – including CDDO and its derivatives CDDO-Im and CDDOMe – inhibit tumor cells growth and induce apoptosis, and they are already being tested on clinical trials in order to be used in cancer therapy [2]. The effects the authors describe are clearly dose-dependent, at high concentration CDDO-Im (250 nM) showed an antiproliferative effect on all lineages, due to an induction of apoptosis, while at low concentrations (10 or 50 nM) the erythroid lineage showed to be the most sensitive regarding cell growth. Regarding cell differentiation, megakaryocytic differentiation is stimulated by all the concentration tested, while erythroid maturation is promoted at low concentrations. Regarding monocytic maturation, CDDO-Im showed no effect or an inhibitory effect, depending on the concentration. It is worth noting that, as Petronelli et al. point in their manuscript, CDDO and its derivatives (CDDO-Im and CDDOMe) induce monocytic and granulocytic differentiation in different leukemic cell lines and also in cells from leukemia patients, what it is in contrast to the results they obtain on normal progenitors. Therefore, the effect of CDDO-Im is not only dependent on the concentration but also on the cellular context. What it is not completely clear yet is the mechanism of action that CDDO-Im follows to induce megakaryocytic differentiation. The authors claim that it must be related to ERK activation and to the regulation of GATA-1 levels. Megakaryopoiesis is a complex process characterized by DNA endoreduplication, cytoplasm maturation and finally platelets release. There are several signaling pathways that intervene in this differentiation process, although the particular contributions of these signaling pathways are not completely understood. However what it is widely accepted, is that a sustained activation of the ERK pathway is absolutely required for the differentiation [3]. Moreover, GATA-1 is the 0145-2126/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2010.10.011
master transcription factor for megakaryo and erythropoiesis. Its levels must be strictly regulated during hematopoiesis, decreasing at the end of both, megakaryo and erythropoiesis. Therefore, if CDDO-Im activates megakaryocytic differentiation, it is not surprising to find the activation of ERK and down-regulation of GATA-1, two phenomena that accompany this differentiation. What it should be determined is whether CDDO-Im triggers these two processes directly or indirectly. Given the different types of cell differentiation stimulated by the CDDO family, and therefore the variety of signaling pathways activated in such processes, it seems unlikely that these triterpenoids affect all these signaling pathways in a direct way. Perhaps all these differentiations follow a common mechanism, then leading to activation of different signaling pathways depending on the cellular context. Such common mechanism could be through Redox signaling. ROS are produced by all types of eukaryotic cells as a consequence of their aerobic metabolism. ROS have been traditionally related to aging, degenerative diseases and cancer. However nowadays it is widely accepted the role of ROS as important second messengers in cell signaling, although the molecular mechanism is not yet completely understood. Tumor cells show higher levels of ROS than healthy cells, which give cancer cells certain advantages, such as a higher growth rate and the capacity to avoid senescence and apoptosis. However, this is a double-edge sword, because if ROS levels increase above a threshold incompatible with cells viability, tumor cells die. Many antitumor treatments take advantage of this situation, and their effectiveness is in part related to an increase of intracellular ROS. Healthy cells show lower levels of ROS, and therefore they would be more resistant to those treatments [4]. CDDO family is being investigated mainly because of its antitumor activity, which seems to be related to an increase of ROS levels [5]. NADPH oxidase ROS production is required for the complete activation of the signaling pathways that control megakaryocytic differentiation, particularly the ERK pathway [6]. Bearing this in mind, it seems likely that CDDO-Im induced megakaryocytic differentiation could be related to an increase of intracellular ROS. Such increase could induce a sustained activation of ERK, what should be enough to trigger megakaryocytic differentiation [3]. Intracellular ROS have been related with the regulation of several signaling pathways. Sometimes the same signaling pathway is activated or inhibited by ROS, depending on the cell type. Therefore, if CDDO family increase ROS levels, the signaling activated might be different from one cell to another, which would explain why these compounds can induce different kinds of cell differentiation. Moreover, the dose-dependent effects found by Petronelli et al. could also be explained by this mechanism, especially the growth
428
Guest editorial / Leukemia Research 35 (2011) 427–428
inhibition found at high concentration, which could be related with an excessive ROS production. The sensitivity of the erythroid lineage to CDDO-Im could be due, either to a bigger ROS increase in these cells or to a bigger sensitivity to ROS of this lineage. Whatever the mechanism of action of CDDO-Im mediating cell differentiation, Petronelli et al. results should be undoubtedly borne in mind if CDDO-Im is eventually use in cancer therapy, because of its effect on normal hematopoietic progenitors differentiation. On the other hand, as the authors propose, CDDO-Im could be used in patient with deficiency of platelets. Nevertheless, if CDDO-Im is eventually used in human therapy, its negative effect on erythroid cells survival and proliferation should not be forgotten. Conflict of interest There is no conflict of interest to be reported. Acknowledgements We thank N. Skinner for reviewing the English version of this paper. Contributions. J.L.S. searched related literature and edited the manuscript; G.L.R.and B.S.S. edited the manuscript and A.H.H. wrote the manuscript. All authors approved the submitting manuscript. References [1] Petronelli A, Pelosi E, Santoro S, Saulle E, Cerio AM, Mariani G, et al. CDDO-Im is a stimulator of megakaryocytic differentiation. Leuk Res 2011;35:534–44.
[2] Yang H, Dou QP. Targeting apoptosis pathway with natural terpenoids: implications for treatment of breast and prostate cancer. Curr Drug Targets 2010;11:733–44. [3] Whalen AM, Galasinski SC, Shapiro PS, Nahreini TS, Ahn NG. Megakaryocytic differentiation induced by constitutive activation of mitogen-activated protein kinase kinase. Mol Cell Biol 1997;17:1947–58. [4] Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROSmediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 2009;8:579–91. [5] Deeb D, Gao X, Jiang H, Janic B, Arbab AS, Rojanasakul Y, et al. Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells through a ROS-dependent mechanism. Biochem Pharmacol 2010;79:350–60. [6] Sardina JL, Lopez-Ruano G, Sanchez-Abarca LI, Perez-Simon JA, Gaztelumendi A, Trigueros C, et al. p22(phox)-dependent NADPH oxidase activity is required for megakaryocytic differentiation. Cell Death Differ 2010;(June), doi:10.1038/cdd.2010.67.
José L. Sardina (BSc) Guillermo López-Ruano (BSc) Beatriz Sánchez-Sánchez (BSc) Angel Hernández-Hernández (PhD) ∗ Department of Biochemistry and Molecular Biology, University of Salamanca, Salamanca, Spain ∗ Corresponding author at: Department of Biochemistry and Molecular Biology, Lab. 106, University of Salamanca, Plaza Doctores de la Reina s/n, 37007, Salamanca, Spain. Tel.: +34 923 294 465; fax: +34 923 294 579. E-mail address: [email protected] (A. Hernández-Hernández)
11 October 2010 Available online 12 November 2010
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Guest editorial
CDDO-Im, an antitumor molecule that also improves platetet production
Keywords: Triterpenoids CDDO-Im Megakaryocytic differentiation ROS
In their study Petronelli et al. [1] describe for the first time that CDDO-Im (cyano-3,12-dioxooleana-1,9 (11)-dien-28-imidazolide), a synthetic derivative of oleanolic acid, induces megakaryocytic differentiation of normal hematopoietic progenitor cells (HPCs). They propose that this drug could be eventually used to increase platelets production in patients with such deficiency. Triterpenoids are a large family of naturally occurring organic molecules (more than 20,000) with a variety of pharmacologic properties. Some of them – including CDDO and its derivatives CDDO-Im and CDDOMe – inhibit tumor cells growth and induce apoptosis, and they are already being tested on clinical trials in order to be used in cancer therapy [2]. The effects the authors describe are clearly dose-dependent, at high concentration CDDO-Im (250 nM) showed an antiproliferative effect on all lineages, due to an induction of apoptosis, while at low concentrations (10 or 50 nM) the erythroid lineage showed to be the most sensitive regarding cell growth. Regarding cell differentiation, megakaryocytic differentiation is stimulated by all the concentration tested, while erythroid maturation is promoted at low concentrations. Regarding monocytic maturation, CDDO-Im showed no effect or an inhibitory effect, depending on the concentration. It is worth noting that, as Petronelli et al. point in their manuscript, CDDO and its derivatives (CDDO-Im and CDDOMe) induce monocytic and granulocytic differentiation in different leukemic cell lines and also in cells from leukemia patients, what it is in contrast to the results they obtain on normal progenitors. Therefore, the effect of CDDO-Im is not only dependent on the concentration but also on the cellular context. What it is not completely clear yet is the mechanism of action that CDDO-Im follows to induce megakaryocytic differentiation. The authors claim that it must be related to ERK activation and to the regulation of GATA-1 levels. Megakaryopoiesis is a complex process characterized by DNA endoreduplication, cytoplasm maturation and finally platelets release. There are several signaling pathways that intervene in this differentiation process, although the particular contributions of these signaling pathways are not completely understood. However what it is widely accepted, is that a sustained activation of the ERK pathway is absolutely required for the differentiation [3]. Moreover, GATA-1 is the 0145-2126/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2010.10.011
master transcription factor for megakaryo and erythropoiesis. Its levels must be strictly regulated during hematopoiesis, decreasing at the end of both, megakaryo and erythropoiesis. Therefore, if CDDO-Im activates megakaryocytic differentiation, it is not surprising to find the activation of ERK and down-regulation of GATA-1, two phenomena that accompany this differentiation. What it should be determined is whether CDDO-Im triggers these two processes directly or indirectly. Given the different types of cell differentiation stimulated by the CDDO family, and therefore the variety of signaling pathways activated in such processes, it seems unlikely that these triterpenoids affect all these signaling pathways in a direct way. Perhaps all these differentiations follow a common mechanism, then leading to activation of different signaling pathways depending on the cellular context. Such common mechanism could be through Redox signaling. ROS are produced by all types of eukaryotic cells as a consequence of their aerobic metabolism. ROS have been traditionally related to aging, degenerative diseases and cancer. However nowadays it is widely accepted the role of ROS as important second messengers in cell signaling, although the molecular mechanism is not yet completely understood. Tumor cells show higher levels of ROS than healthy cells, which give cancer cells certain advantages, such as a higher growth rate and the capacity to avoid senescence and apoptosis. However, this is a double-edge sword, because if ROS levels increase above a threshold incompatible with cells viability, tumor cells die. Many antitumor treatments take advantage of this situation, and their effectiveness is in part related to an increase of intracellular ROS. Healthy cells show lower levels of ROS, and therefore they would be more resistant to those treatments [4]. CDDO family is being investigated mainly because of its antitumor activity, which seems to be related to an increase of ROS levels [5]. NADPH oxidase ROS production is required for the complete activation of the signaling pathways that control megakaryocytic differentiation, particularly the ERK pathway [6]. Bearing this in mind, it seems likely that CDDO-Im induced megakaryocytic differentiation could be related to an increase of intracellular ROS. Such increase could induce a sustained activation of ERK, what should be enough to trigger megakaryocytic differentiation [3]. Intracellular ROS have been related with the regulation of several signaling pathways. Sometimes the same signaling pathway is activated or inhibited by ROS, depending on the cell type. Therefore, if CDDO family increase ROS levels, the signaling activated might be different from one cell to another, which would explain why these compounds can induce different kinds of cell differentiation. Moreover, the dose-dependent effects found by Petronelli et al. could also be explained by this mechanism, especially the growth
428
Guest editorial / Leukemia Research 35 (2011) 427–428
inhibition found at high concentration, which could be related with an excessive ROS production. The sensitivity of the erythroid lineage to CDDO-Im could be due, either to a bigger ROS increase in these cells or to a bigger sensitivity to ROS of this lineage. Whatever the mechanism of action of CDDO-Im mediating cell differentiation, Petronelli et al. results should be undoubtedly borne in mind if CDDO-Im is eventually use in cancer therapy, because of its effect on normal hematopoietic progenitors differentiation. On the other hand, as the authors propose, CDDO-Im could be used in patient with deficiency of platelets. Nevertheless, if CDDO-Im is eventually used in human therapy, its negative effect on erythroid cells survival and proliferation should not be forgotten. Conflict of interest There is no conflict of interest to be reported. Acknowledgements We thank N. Skinner for reviewing the English version of this paper. Contributions. J.L.S. searched related literature and edited the manuscript; G.L.R.and B.S.S. edited the manuscript and A.H.H. wrote the manuscript. All authors approved the submitting manuscript. References [1] Petronelli A, Pelosi E, Santoro S, Saulle E, Cerio AM, Mariani G, et al. CDDO-Im is a stimulator of megakaryocytic differentiation. Leuk Res 2011;35:534–44.
[2] Yang H, Dou QP. Targeting apoptosis pathway with natural terpenoids: implications for treatment of breast and prostate cancer. Curr Drug Targets 2010;11:733–44. [3] Whalen AM, Galasinski SC, Shapiro PS, Nahreini TS, Ahn NG. Megakaryocytic differentiation induced by constitutive activation of mitogen-activated protein kinase kinase. Mol Cell Biol 1997;17:1947–58. [4] Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROSmediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 2009;8:579–91. [5] Deeb D, Gao X, Jiang H, Janic B, Arbab AS, Rojanasakul Y, et al. Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells through a ROS-dependent mechanism. Biochem Pharmacol 2010;79:350–60. [6] Sardina JL, Lopez-Ruano G, Sanchez-Abarca LI, Perez-Simon JA, Gaztelumendi A, Trigueros C, et al. p22(phox)-dependent NADPH oxidase activity is required for megakaryocytic differentiation. Cell Death Differ 2010;(June), doi:10.1038/cdd.2010.67.
José L. Sardina (BSc) Guillermo López-Ruano (BSc) Beatriz Sánchez-Sánchez (BSc) Angel Hernández-Hernández (PhD) ∗ Department of Biochemistry and Molecular Biology, University of Salamanca, Salamanca, Spain ∗ Corresponding author at: Department of Biochemistry and Molecular Biology, Lab. 106, University of Salamanca, Plaza Doctores de la Reina s/n, 37007, Salamanca, Spain. Tel.: +34 923 294 465; fax: +34 923 294 579. E-mail address: [email protected] (A. Hernández-Hernández)
11 October 2010 Available online 12 November 2010