The Experts below are selected from a list of 102 Experts worldwide ranked by ideXlab platform
Srdan Verstovsek - One of the best experts on this subject based on the ideXlab platform.
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The organic Arsenic Derivative GMZ27 induces PML-RARα-independent apoptosis in myeloid leukemia cells.
Anticancer research, 2012Co-Authors: Xiaodong Cheng, Alfonso Quintás-cardama, Emil J. Freireich, Ralph A. Zingaro, Hagop M. Kantarjian, Mirna Golemović, Ming-zhang Gao, Michael Andreeff, Srdan VerstovsekAbstract:Arsenic trioxide (ATO) is an inorganic Arsenic Derivative that is very effective against acute promyelocytic leukemia. However, organic Arsenic Derivatives (OAD) have a more favorable toxicity profile than ATO. We herein characterized dipropil-S-glycerol Arsenic (GMZ27), a novel OAD. GMZ27 had potent antiproliferative activity against human acute myeloid leukemia (AML) cell lines that was higher than that of ATO. In contrast to ATO, GMZ27 only marginally induced maturation of leukemia cells and had no effect on the cell cycle. The anti-leukemia activity of GMZ27 against AML cells was independent of the presence of the PML-RARα fusion protein. GMZ27 dissipates mitochondrial transmembrane potential, and induces cleavage of caspase 9 and activation of caspase 3 without altering the expression levels of (BCL-2), BAX and BCL-xl. GMZ27 induces the formation of intracellular superoxide, a reactive oxygen species (ROS) which plays a major role in the antileukemia activity of this OAD. In addition to ROS generation, GMZ27 concomitantly reduces intracellular glutathione which markedly weakens the cellular antioxidant capacity, thus enhancing the detrimental intracellular effects of ROS production. These results indicate that GMZ27 induces apoptosis in AML cells in a PML-RARα-independent fashion, through the induction of ROS production. This activity provides the rationale for the testing of GMZ27 in patients with AML. Several studies conducted over the past decade established the efficacy of Arsenic trioxide (ATO) in patients with both newly diagnosed or relapsed acute promyeloytic leukemia (APL) (1- 3). The success of ATO in inducing high rates of complete remission in patients who have relapsed with this, once highly
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MER1, a novel organic Arsenic Derivative, has potent PML-RARα- independent cytotoxic activity against leukemia cells
Investigational New Drugs, 2010Co-Authors: Mirna Golemovic, Alfonso Quintás-cardama, Taghi Manshouri, Nada Orsolic, Hatice Duzkale, Mary Johansen, Emil J. Freireich, Hagop Kantarjian, Ralph A. Zingaro, Srdan VerstovsekAbstract:Arsenic trioxide (ATO) is an inorganic Arsenic Derivative that is highly effective against PML-RARα -positive leukemia but much less against other hematological malignancies. We synthesized an organic Arsenic Derivative (OAD), S-dimethylarsino-thiosuccinic acid (MER1), which offers a superior toxicity profile and comparable in vitro activity relative to ATO. In Swiss Webster mice, maximally-tolerated cumulative dose of MER1 when given IV for 5 days was 100 mg/kg/d. We demonstrated that MER1 induced apoptosis and dose- and time-dependent inhibition of survival and growth in a panel of myeloid leukemia cell lines. Unlike ATO, this activity was independent of PML-RARα status and was not associated with induction of myeloid maturation. In NB4 and HL60 cells, MER1 and ATO induced caspase activation and dissipation of mitochondrial transmembrane potential. At the same time, MER1 induced generation of reactive oxygen species (ROS) and cell cycle arrest in G2/M phase and proved to be more potent than ATO at inducing apoptosis. ROS generation and intracellular glutathione levels were key modulators of MER1-induced cytotoxicity as evidenced by abrogation of apoptosis in myeloid leukemia cell lines pretreated with the disulfide bond-reducing agent dithiothreitol or the radical scavenger N-acetyl-L-cysteine. Collectively, these data indicate that MER1 induces apoptosis in PML-RARα -positive and -negative myeloid leukemia cells by enhancing oxidative stress. This agent, therefore, combines low in vivo toxicity with formidable in vitro pro-apoptotic ROS-mediated activity, and may represent a novel OAD suitable for clinical development against a variety of hematological malignancies.
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Chemical and clinical development of darinaparsin, a novel organic Arsenic Derivative.
Anti-cancer agents in medicinal chemistry, 2008Co-Authors: Alfonso Quintás-cardama, Srdan Verstovsek, Emil Freireich, Hagop M. Kantarjian, Yiwen Chen, Ralph A. ZingaroAbstract:The inorganic Arsenic Derivative Arsenic trioxide (ATO) has proven to be highly efficacious in patients with acute promyelocytic leukemia (APL) and has been associated with complete cytogenetic response in most treated patients diagnosed with this disease. This is due to ATOs direct effect on PML-RARα oncoprotein patognomonic for APL. ATO has shown moderate activity against certain other hematologic and solid organ malignancies but is also associated with significant toxicities, especially when used at higher doses. The development of orally bioavailable organic Arsenic Derivatives (OAD) offering improved toxicity profiles and better efficacy may expand the use of Arsenic Derivatives in hematologic malignancies and solid tumors. The favorable in vivo carcinostatic activity of S-dimethylarsino-thioglucose, the first OAD synthesized in murine leukemia models by our group in 1975, set the stage for our efforts to develop OADs. Unfortunately, the program remained dormant for almost two decades. The success of ATO in APL in the late 1990s re-ignited the interest in the use of OADs in cancer chemotherapy. This review describes the chemical development of OADs and summarizes the clinical development of a promising lead compound, Darinaparsin (ZIO-101; SGLU; S-dimethylarsino-glutathione), for the treatment of a variety of cancers.
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comparison of uptake and intracellular induced structural changes of Arsenic trioxide an inorganic compound and organic Arsenic Derivative s dimethylarsino glutathione sglu zio 101 in nb4 acute promyelocytic leukemia apl cells
Blood, 2005Co-Authors: Taghi Manshouri, Emil J. Freireich, Ralph A. Zingaro, Hagop M. Kantarjian, Michael Andreeff, Subbarao V Kala, Faramarz Ashoori, Srdan VerstovsekAbstract:Arsenic trioxide (As 2 O 3 ; ATO) inhibits proliferation and induces apoptosis of APL cells. However, little is known about the intracellular structural changes associated with Arsenic exposure. We studied effects of 2 Arsenic compounds, ATO and S-dimethylarsino-glutathione (SGLU; ZIO-101) on NB4 APL cells. ZIO-101 is novel water-soluble organic Arsenic Derivative currently in Phase I clinical studies. Exposure of cancer cells to ZIO-101 results in G2/M cell cycle arrest and apoptosis. NB4 cells were exposed to 10, 50, 100 and 250 μM ZIO-101 or ATO for 1 h and intracellular Arsenic content was determined by inductively coupled plasma mass spectrometry (ICP/MS). ZIO-101-treated cells contained 5–8 fold more Arsenic then ATO-treated cells. Electron microscopy of NB4 cells exposed to 1 μM ZIO-101 or ATO for 24–72 h revealed different structural changes. ATO treated cells showed time-dependent mitochondrial hypotrophy and apoptosis, including cytoplasmic vacuolization, nuclear condensation and cell blebs. In contrast, ZIO-101 treated cells showed time-dependent mitochondrial atrophy, mitochondrial matrix condensation, and apoptosis. These data suggest that ZIO-101 is more specific mitochondrial toxin than ATO. Studies are in progress to understand the exact mechanism through which ZIO-101 affects mitochondria. Because these Arsenic Derivatives have different mechanism of action they may have different spectrums of activity against cancers; this should be tested in clinical trials.
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Mechanisms of increased reactive oxygen species (ROS) generation induced by organic Arsenic Derivative S-dimethylarsino-glutathione (SGLU ; ZIO-101).
Blood, 2005Co-Authors: Xiaodong Cheng, Emil J. Freireich, Ralph A. Zingaro, Hagop M. Kantarjian, Mirna Golemović, Michael Andreeff, Manshouri Taghi, Peng Huang, Srdan VerstovsekAbstract:ZIO-101 is organic Arsenic with similar anti-leukemia activity to Arsenic trioxide (ATO) but much less toxicity. Consequently, ZIO-101 can be given at substantially higher doses than ATO and may be active in more diverse cancers than ATO. The precise anti-cancer mechanism of ZIO-101 is unknown: ZIO-101 increases intracellular production of reactive oxygen species (ROS) in dose dependent manner, resulting in apoptosis of leukemic cells. Modifying intracellular ROS levels alters the ability of ZIO-101 to induce apoptosis. We focused on the 2 most important intracellular ROS generators, mitochondria and NADPH oxidase. Cells were treated with ZIO-101 and NADPH oxidase expression levels, membrane translocation and interactions of subunits were studied. Effects of modified NADPH oxidase levels on ZIO-101-induced ROS production were studied (diphenyleneiodonium [DPI], a specific inhibitor of NADPH oxidase, and SiRNA technique were used to inhibit enzyme function, while bryostatin-1, a specific activator of NADPH oxidase, was used to increase enzyme function). Mitochondrial DNA-depleted HL60 Rho-0 cells were also used to evaluate mitochondrial input to ROS-generation. Our data show that ZIO-101 activates NADPH oxidase. A low concentration of ZIO-101 (1uM) requires 14 h to significantly increase intracellular ROS levels and kill leukemic cell. This effect is strongly inhibited by DPI-pretreatment and is also seen in P47-SiRNA transfected HL60 cells. On the other hand, this A higher dose of ZIO-101 (4uM) increases ROS levels more rapidly (2-6 h). This early increase is not inhibited by DPI-pretreatment or SiRNA transfection. A 14 h but not 2-6 h increase in ROS is detectable in Rho-0 HL60 cells. These data indicate dose-dependent mechanisms of ZIO-101 induction of ROS: (1) 1uM ZIO-101 induces NADPH oxidase activity which results in ROS production detectable at 14 h ; there is no mitochondrial component ; (2) 4uM ZIO-101 disrupts mitochondrial function resulting in an earlier increase in ROS levels and subsequent apoptosis. effect is significantly enhanced in cells that have increased enzyme function. ROS-production in Rho-0 HL60 cells is unaffected by these interventions.
Ralph A. Zingaro - One of the best experts on this subject based on the ideXlab platform.
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The organic Arsenic Derivative GMZ27 induces PML-RARα-independent apoptosis in myeloid leukemia cells.
Anticancer research, 2012Co-Authors: Xiaodong Cheng, Alfonso Quintás-cardama, Emil J. Freireich, Ralph A. Zingaro, Hagop M. Kantarjian, Mirna Golemović, Ming-zhang Gao, Michael Andreeff, Srdan VerstovsekAbstract:Arsenic trioxide (ATO) is an inorganic Arsenic Derivative that is very effective against acute promyelocytic leukemia. However, organic Arsenic Derivatives (OAD) have a more favorable toxicity profile than ATO. We herein characterized dipropil-S-glycerol Arsenic (GMZ27), a novel OAD. GMZ27 had potent antiproliferative activity against human acute myeloid leukemia (AML) cell lines that was higher than that of ATO. In contrast to ATO, GMZ27 only marginally induced maturation of leukemia cells and had no effect on the cell cycle. The anti-leukemia activity of GMZ27 against AML cells was independent of the presence of the PML-RARα fusion protein. GMZ27 dissipates mitochondrial transmembrane potential, and induces cleavage of caspase 9 and activation of caspase 3 without altering the expression levels of (BCL-2), BAX and BCL-xl. GMZ27 induces the formation of intracellular superoxide, a reactive oxygen species (ROS) which plays a major role in the antileukemia activity of this OAD. In addition to ROS generation, GMZ27 concomitantly reduces intracellular glutathione which markedly weakens the cellular antioxidant capacity, thus enhancing the detrimental intracellular effects of ROS production. These results indicate that GMZ27 induces apoptosis in AML cells in a PML-RARα-independent fashion, through the induction of ROS production. This activity provides the rationale for the testing of GMZ27 in patients with AML. Several studies conducted over the past decade established the efficacy of Arsenic trioxide (ATO) in patients with both newly diagnosed or relapsed acute promyeloytic leukemia (APL) (1- 3). The success of ATO in inducing high rates of complete remission in patients who have relapsed with this, once highly
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MER1, a novel organic Arsenic Derivative, has potent PML-RARα- independent cytotoxic activity against leukemia cells
Investigational New Drugs, 2010Co-Authors: Mirna Golemovic, Alfonso Quintás-cardama, Taghi Manshouri, Nada Orsolic, Hatice Duzkale, Mary Johansen, Emil J. Freireich, Hagop Kantarjian, Ralph A. Zingaro, Srdan VerstovsekAbstract:Arsenic trioxide (ATO) is an inorganic Arsenic Derivative that is highly effective against PML-RARα -positive leukemia but much less against other hematological malignancies. We synthesized an organic Arsenic Derivative (OAD), S-dimethylarsino-thiosuccinic acid (MER1), which offers a superior toxicity profile and comparable in vitro activity relative to ATO. In Swiss Webster mice, maximally-tolerated cumulative dose of MER1 when given IV for 5 days was 100 mg/kg/d. We demonstrated that MER1 induced apoptosis and dose- and time-dependent inhibition of survival and growth in a panel of myeloid leukemia cell lines. Unlike ATO, this activity was independent of PML-RARα status and was not associated with induction of myeloid maturation. In NB4 and HL60 cells, MER1 and ATO induced caspase activation and dissipation of mitochondrial transmembrane potential. At the same time, MER1 induced generation of reactive oxygen species (ROS) and cell cycle arrest in G2/M phase and proved to be more potent than ATO at inducing apoptosis. ROS generation and intracellular glutathione levels were key modulators of MER1-induced cytotoxicity as evidenced by abrogation of apoptosis in myeloid leukemia cell lines pretreated with the disulfide bond-reducing agent dithiothreitol or the radical scavenger N-acetyl-L-cysteine. Collectively, these data indicate that MER1 induces apoptosis in PML-RARα -positive and -negative myeloid leukemia cells by enhancing oxidative stress. This agent, therefore, combines low in vivo toxicity with formidable in vitro pro-apoptotic ROS-mediated activity, and may represent a novel OAD suitable for clinical development against a variety of hematological malignancies.
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Chemical and clinical development of darinaparsin, a novel organic Arsenic Derivative.
Anti-cancer agents in medicinal chemistry, 2008Co-Authors: Alfonso Quintás-cardama, Srdan Verstovsek, Emil Freireich, Hagop M. Kantarjian, Yiwen Chen, Ralph A. ZingaroAbstract:The inorganic Arsenic Derivative Arsenic trioxide (ATO) has proven to be highly efficacious in patients with acute promyelocytic leukemia (APL) and has been associated with complete cytogenetic response in most treated patients diagnosed with this disease. This is due to ATOs direct effect on PML-RARα oncoprotein patognomonic for APL. ATO has shown moderate activity against certain other hematologic and solid organ malignancies but is also associated with significant toxicities, especially when used at higher doses. The development of orally bioavailable organic Arsenic Derivatives (OAD) offering improved toxicity profiles and better efficacy may expand the use of Arsenic Derivatives in hematologic malignancies and solid tumors. The favorable in vivo carcinostatic activity of S-dimethylarsino-thioglucose, the first OAD synthesized in murine leukemia models by our group in 1975, set the stage for our efforts to develop OADs. Unfortunately, the program remained dormant for almost two decades. The success of ATO in APL in the late 1990s re-ignited the interest in the use of OADs in cancer chemotherapy. This review describes the chemical development of OADs and summarizes the clinical development of a promising lead compound, Darinaparsin (ZIO-101; SGLU; S-dimethylarsino-glutathione), for the treatment of a variety of cancers.
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comparison of uptake and intracellular induced structural changes of Arsenic trioxide an inorganic compound and organic Arsenic Derivative s dimethylarsino glutathione sglu zio 101 in nb4 acute promyelocytic leukemia apl cells
Blood, 2005Co-Authors: Taghi Manshouri, Emil J. Freireich, Ralph A. Zingaro, Hagop M. Kantarjian, Michael Andreeff, Subbarao V Kala, Faramarz Ashoori, Srdan VerstovsekAbstract:Arsenic trioxide (As 2 O 3 ; ATO) inhibits proliferation and induces apoptosis of APL cells. However, little is known about the intracellular structural changes associated with Arsenic exposure. We studied effects of 2 Arsenic compounds, ATO and S-dimethylarsino-glutathione (SGLU; ZIO-101) on NB4 APL cells. ZIO-101 is novel water-soluble organic Arsenic Derivative currently in Phase I clinical studies. Exposure of cancer cells to ZIO-101 results in G2/M cell cycle arrest and apoptosis. NB4 cells were exposed to 10, 50, 100 and 250 μM ZIO-101 or ATO for 1 h and intracellular Arsenic content was determined by inductively coupled plasma mass spectrometry (ICP/MS). ZIO-101-treated cells contained 5–8 fold more Arsenic then ATO-treated cells. Electron microscopy of NB4 cells exposed to 1 μM ZIO-101 or ATO for 24–72 h revealed different structural changes. ATO treated cells showed time-dependent mitochondrial hypotrophy and apoptosis, including cytoplasmic vacuolization, nuclear condensation and cell blebs. In contrast, ZIO-101 treated cells showed time-dependent mitochondrial atrophy, mitochondrial matrix condensation, and apoptosis. These data suggest that ZIO-101 is more specific mitochondrial toxin than ATO. Studies are in progress to understand the exact mechanism through which ZIO-101 affects mitochondria. Because these Arsenic Derivatives have different mechanism of action they may have different spectrums of activity against cancers; this should be tested in clinical trials.
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Mechanisms of increased reactive oxygen species (ROS) generation induced by organic Arsenic Derivative S-dimethylarsino-glutathione (SGLU ; ZIO-101).
Blood, 2005Co-Authors: Xiaodong Cheng, Emil J. Freireich, Ralph A. Zingaro, Hagop M. Kantarjian, Mirna Golemović, Michael Andreeff, Manshouri Taghi, Peng Huang, Srdan VerstovsekAbstract:ZIO-101 is organic Arsenic with similar anti-leukemia activity to Arsenic trioxide (ATO) but much less toxicity. Consequently, ZIO-101 can be given at substantially higher doses than ATO and may be active in more diverse cancers than ATO. The precise anti-cancer mechanism of ZIO-101 is unknown: ZIO-101 increases intracellular production of reactive oxygen species (ROS) in dose dependent manner, resulting in apoptosis of leukemic cells. Modifying intracellular ROS levels alters the ability of ZIO-101 to induce apoptosis. We focused on the 2 most important intracellular ROS generators, mitochondria and NADPH oxidase. Cells were treated with ZIO-101 and NADPH oxidase expression levels, membrane translocation and interactions of subunits were studied. Effects of modified NADPH oxidase levels on ZIO-101-induced ROS production were studied (diphenyleneiodonium [DPI], a specific inhibitor of NADPH oxidase, and SiRNA technique were used to inhibit enzyme function, while bryostatin-1, a specific activator of NADPH oxidase, was used to increase enzyme function). Mitochondrial DNA-depleted HL60 Rho-0 cells were also used to evaluate mitochondrial input to ROS-generation. Our data show that ZIO-101 activates NADPH oxidase. A low concentration of ZIO-101 (1uM) requires 14 h to significantly increase intracellular ROS levels and kill leukemic cell. This effect is strongly inhibited by DPI-pretreatment and is also seen in P47-SiRNA transfected HL60 cells. On the other hand, this A higher dose of ZIO-101 (4uM) increases ROS levels more rapidly (2-6 h). This early increase is not inhibited by DPI-pretreatment or SiRNA transfection. A 14 h but not 2-6 h increase in ROS is detectable in Rho-0 HL60 cells. These data indicate dose-dependent mechanisms of ZIO-101 induction of ROS: (1) 1uM ZIO-101 induces NADPH oxidase activity which results in ROS production detectable at 14 h ; there is no mitochondrial component ; (2) 4uM ZIO-101 disrupts mitochondrial function resulting in an earlier increase in ROS levels and subsequent apoptosis. effect is significantly enhanced in cells that have increased enzyme function. ROS-production in Rho-0 HL60 cells is unaffected by these interventions.
Emil J. Freireich - One of the best experts on this subject based on the ideXlab platform.
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The organic Arsenic Derivative GMZ27 induces PML-RARα-independent apoptosis in myeloid leukemia cells.
Anticancer research, 2012Co-Authors: Xiaodong Cheng, Alfonso Quintás-cardama, Emil J. Freireich, Ralph A. Zingaro, Hagop M. Kantarjian, Mirna Golemović, Ming-zhang Gao, Michael Andreeff, Srdan VerstovsekAbstract:Arsenic trioxide (ATO) is an inorganic Arsenic Derivative that is very effective against acute promyelocytic leukemia. However, organic Arsenic Derivatives (OAD) have a more favorable toxicity profile than ATO. We herein characterized dipropil-S-glycerol Arsenic (GMZ27), a novel OAD. GMZ27 had potent antiproliferative activity against human acute myeloid leukemia (AML) cell lines that was higher than that of ATO. In contrast to ATO, GMZ27 only marginally induced maturation of leukemia cells and had no effect on the cell cycle. The anti-leukemia activity of GMZ27 against AML cells was independent of the presence of the PML-RARα fusion protein. GMZ27 dissipates mitochondrial transmembrane potential, and induces cleavage of caspase 9 and activation of caspase 3 without altering the expression levels of (BCL-2), BAX and BCL-xl. GMZ27 induces the formation of intracellular superoxide, a reactive oxygen species (ROS) which plays a major role in the antileukemia activity of this OAD. In addition to ROS generation, GMZ27 concomitantly reduces intracellular glutathione which markedly weakens the cellular antioxidant capacity, thus enhancing the detrimental intracellular effects of ROS production. These results indicate that GMZ27 induces apoptosis in AML cells in a PML-RARα-independent fashion, through the induction of ROS production. This activity provides the rationale for the testing of GMZ27 in patients with AML. Several studies conducted over the past decade established the efficacy of Arsenic trioxide (ATO) in patients with both newly diagnosed or relapsed acute promyeloytic leukemia (APL) (1- 3). The success of ATO in inducing high rates of complete remission in patients who have relapsed with this, once highly
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MER1, a novel organic Arsenic Derivative, has potent PML-RARα- independent cytotoxic activity against leukemia cells
Investigational New Drugs, 2010Co-Authors: Mirna Golemovic, Alfonso Quintás-cardama, Taghi Manshouri, Nada Orsolic, Hatice Duzkale, Mary Johansen, Emil J. Freireich, Hagop Kantarjian, Ralph A. Zingaro, Srdan VerstovsekAbstract:Arsenic trioxide (ATO) is an inorganic Arsenic Derivative that is highly effective against PML-RARα -positive leukemia but much less against other hematological malignancies. We synthesized an organic Arsenic Derivative (OAD), S-dimethylarsino-thiosuccinic acid (MER1), which offers a superior toxicity profile and comparable in vitro activity relative to ATO. In Swiss Webster mice, maximally-tolerated cumulative dose of MER1 when given IV for 5 days was 100 mg/kg/d. We demonstrated that MER1 induced apoptosis and dose- and time-dependent inhibition of survival and growth in a panel of myeloid leukemia cell lines. Unlike ATO, this activity was independent of PML-RARα status and was not associated with induction of myeloid maturation. In NB4 and HL60 cells, MER1 and ATO induced caspase activation and dissipation of mitochondrial transmembrane potential. At the same time, MER1 induced generation of reactive oxygen species (ROS) and cell cycle arrest in G2/M phase and proved to be more potent than ATO at inducing apoptosis. ROS generation and intracellular glutathione levels were key modulators of MER1-induced cytotoxicity as evidenced by abrogation of apoptosis in myeloid leukemia cell lines pretreated with the disulfide bond-reducing agent dithiothreitol or the radical scavenger N-acetyl-L-cysteine. Collectively, these data indicate that MER1 induces apoptosis in PML-RARα -positive and -negative myeloid leukemia cells by enhancing oxidative stress. This agent, therefore, combines low in vivo toxicity with formidable in vitro pro-apoptotic ROS-mediated activity, and may represent a novel OAD suitable for clinical development against a variety of hematological malignancies.
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comparison of uptake and intracellular induced structural changes of Arsenic trioxide an inorganic compound and organic Arsenic Derivative s dimethylarsino glutathione sglu zio 101 in nb4 acute promyelocytic leukemia apl cells
Blood, 2005Co-Authors: Taghi Manshouri, Emil J. Freireich, Ralph A. Zingaro, Hagop M. Kantarjian, Michael Andreeff, Subbarao V Kala, Faramarz Ashoori, Srdan VerstovsekAbstract:Arsenic trioxide (As 2 O 3 ; ATO) inhibits proliferation and induces apoptosis of APL cells. However, little is known about the intracellular structural changes associated with Arsenic exposure. We studied effects of 2 Arsenic compounds, ATO and S-dimethylarsino-glutathione (SGLU; ZIO-101) on NB4 APL cells. ZIO-101 is novel water-soluble organic Arsenic Derivative currently in Phase I clinical studies. Exposure of cancer cells to ZIO-101 results in G2/M cell cycle arrest and apoptosis. NB4 cells were exposed to 10, 50, 100 and 250 μM ZIO-101 or ATO for 1 h and intracellular Arsenic content was determined by inductively coupled plasma mass spectrometry (ICP/MS). ZIO-101-treated cells contained 5–8 fold more Arsenic then ATO-treated cells. Electron microscopy of NB4 cells exposed to 1 μM ZIO-101 or ATO for 24–72 h revealed different structural changes. ATO treated cells showed time-dependent mitochondrial hypotrophy and apoptosis, including cytoplasmic vacuolization, nuclear condensation and cell blebs. In contrast, ZIO-101 treated cells showed time-dependent mitochondrial atrophy, mitochondrial matrix condensation, and apoptosis. These data suggest that ZIO-101 is more specific mitochondrial toxin than ATO. Studies are in progress to understand the exact mechanism through which ZIO-101 affects mitochondria. Because these Arsenic Derivatives have different mechanism of action they may have different spectrums of activity against cancers; this should be tested in clinical trials.
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Mechanisms of increased reactive oxygen species (ROS) generation induced by organic Arsenic Derivative S-dimethylarsino-glutathione (SGLU ; ZIO-101).
Blood, 2005Co-Authors: Xiaodong Cheng, Emil J. Freireich, Ralph A. Zingaro, Hagop M. Kantarjian, Mirna Golemović, Michael Andreeff, Manshouri Taghi, Peng Huang, Srdan VerstovsekAbstract:ZIO-101 is organic Arsenic with similar anti-leukemia activity to Arsenic trioxide (ATO) but much less toxicity. Consequently, ZIO-101 can be given at substantially higher doses than ATO and may be active in more diverse cancers than ATO. The precise anti-cancer mechanism of ZIO-101 is unknown: ZIO-101 increases intracellular production of reactive oxygen species (ROS) in dose dependent manner, resulting in apoptosis of leukemic cells. Modifying intracellular ROS levels alters the ability of ZIO-101 to induce apoptosis. We focused on the 2 most important intracellular ROS generators, mitochondria and NADPH oxidase. Cells were treated with ZIO-101 and NADPH oxidase expression levels, membrane translocation and interactions of subunits were studied. Effects of modified NADPH oxidase levels on ZIO-101-induced ROS production were studied (diphenyleneiodonium [DPI], a specific inhibitor of NADPH oxidase, and SiRNA technique were used to inhibit enzyme function, while bryostatin-1, a specific activator of NADPH oxidase, was used to increase enzyme function). Mitochondrial DNA-depleted HL60 Rho-0 cells were also used to evaluate mitochondrial input to ROS-generation. Our data show that ZIO-101 activates NADPH oxidase. A low concentration of ZIO-101 (1uM) requires 14 h to significantly increase intracellular ROS levels and kill leukemic cell. This effect is strongly inhibited by DPI-pretreatment and is also seen in P47-SiRNA transfected HL60 cells. On the other hand, this A higher dose of ZIO-101 (4uM) increases ROS levels more rapidly (2-6 h). This early increase is not inhibited by DPI-pretreatment or SiRNA transfection. A 14 h but not 2-6 h increase in ROS is detectable in Rho-0 HL60 cells. These data indicate dose-dependent mechanisms of ZIO-101 induction of ROS: (1) 1uM ZIO-101 induces NADPH oxidase activity which results in ROS production detectable at 14 h ; there is no mitochondrial component ; (2) 4uM ZIO-101 disrupts mitochondrial function resulting in an earlier increase in ROS levels and subsequent apoptosis. effect is significantly enhanced in cells that have increased enzyme function. ROS-production in Rho-0 HL60 cells is unaffected by these interventions.
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Organic Arsenic Lipid Derivatives Are More Potent and Less Toxic Than Inorganic Arsenic Trioxide in Preclinical Testing.
Blood, 2004Co-Authors: Xiaodong Cheng, Emil J. Freireich, Ralph A. Zingaro, Hagop M. Kantarjian, Mirna Golemović, Ming-zhang Gao, Michael Andreeff, Francis J. Giles, Srdan VerstovsekAbstract:Arsenic trioxide (ATO) is an inorganic Arsenic Derivative that is effective in patients with relapsed acute promyelocytic leukemia. It is being investigated as therapy for other cancers but the risk/benefit ratio for its use still has to be determined due to its significant side effects. In contrast, organic Arsenic Derivatives are known to be much less toxic. We have synthesized a series of eight organic Arsenic lipid Derivatives and have tested them in NIH 60 cell line screen. Based on its activity, we selected GMZ27 [3-S-di(n-propyl)arsino-3-thio-1,2-propanediol] for further study in our laboratory and have confirmed its potent activity against human acute myeloid leukemia cell lines HL60 and NB4, which was significantly higher than that of Arsenic trioxide. The IC50 (concentration that kills 50% of the cells) in MTS assay is 0.5 and 0.9 μm for GMZ27. Assessment of the mechanisms of action of GMZ27 in cell lines has shown that the GMZ27 was more potent inducer of superoxide than ATO. GMZ27 caused dissipation of mitochondrial transmembrane potential, cleavage of caspase 9, caspase 3 activation, PARP cleavage, and compromise in cell membrane integrity. However, its treatment also resulted in caspase 8 cleavage, suggesting that it affects both intrinsic and extrinsic apoptotic pathway. Its activity was related to the level of glutathione in the leukemic cells as pretreatment of the cells with BSO, which depletes intracellular glutathione, results in cells sensitivity to GMZ27. On the other hand, pretreatment with DDT, which increases intracellular glutathione, results in their resistance to GMZ27. GMZ27 had no effect on cells maturation and differentiation, and cell cycle. GMZ27 when tested against healthy donor mononuclear cells in a colony forming assay showed significantly less toxicity than Arsenic trioxide. In vivo toxicity testing in Swiss Webster mice showed LD50 (dose that kills 50% of mice) to be 100 mg/kg for GMZ27, comparing to 10 mg/kg for ATO. In conclusion, organic Arsenic lipid Derivatives, and in particular GMZ27, may have more potent antileukemic activity and significantly less toxicity in vivo and in vitro than ATO and therefore further development of these medications is warranted.
Gordon W. Moran - One of the best experts on this subject based on the ideXlab platform.
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Acetarsol in the management of mesalazine-refractory ulcerative proctitis: a tertiary-level care experience.
European journal of gastroenterology & hepatology, 2019Co-Authors: Konstantinos Argyriou, Sunil Samuel, Gordon W. MoranAbstract:BackgroundMesalazine-refractory ulcerative proctitis is common, with a significant proportion of the patients requiring escalation to immunomodulators or biological therapy. Three small preliminary cohort studies suggested good clinical efficacy for the organic Arsenic Derivative acetarsol in the ma
Alfonso Quintás-cardama - One of the best experts on this subject based on the ideXlab platform.
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The organic Arsenic Derivative GMZ27 induces PML-RARα-independent apoptosis in myeloid leukemia cells.
Anticancer research, 2012Co-Authors: Xiaodong Cheng, Alfonso Quintás-cardama, Emil J. Freireich, Ralph A. Zingaro, Hagop M. Kantarjian, Mirna Golemović, Ming-zhang Gao, Michael Andreeff, Srdan VerstovsekAbstract:Arsenic trioxide (ATO) is an inorganic Arsenic Derivative that is very effective against acute promyelocytic leukemia. However, organic Arsenic Derivatives (OAD) have a more favorable toxicity profile than ATO. We herein characterized dipropil-S-glycerol Arsenic (GMZ27), a novel OAD. GMZ27 had potent antiproliferative activity against human acute myeloid leukemia (AML) cell lines that was higher than that of ATO. In contrast to ATO, GMZ27 only marginally induced maturation of leukemia cells and had no effect on the cell cycle. The anti-leukemia activity of GMZ27 against AML cells was independent of the presence of the PML-RARα fusion protein. GMZ27 dissipates mitochondrial transmembrane potential, and induces cleavage of caspase 9 and activation of caspase 3 without altering the expression levels of (BCL-2), BAX and BCL-xl. GMZ27 induces the formation of intracellular superoxide, a reactive oxygen species (ROS) which plays a major role in the antileukemia activity of this OAD. In addition to ROS generation, GMZ27 concomitantly reduces intracellular glutathione which markedly weakens the cellular antioxidant capacity, thus enhancing the detrimental intracellular effects of ROS production. These results indicate that GMZ27 induces apoptosis in AML cells in a PML-RARα-independent fashion, through the induction of ROS production. This activity provides the rationale for the testing of GMZ27 in patients with AML. Several studies conducted over the past decade established the efficacy of Arsenic trioxide (ATO) in patients with both newly diagnosed or relapsed acute promyeloytic leukemia (APL) (1- 3). The success of ATO in inducing high rates of complete remission in patients who have relapsed with this, once highly
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MER1, a novel organic Arsenic Derivative, has potent PML-RARα- independent cytotoxic activity against leukemia cells
Investigational New Drugs, 2010Co-Authors: Mirna Golemovic, Alfonso Quintás-cardama, Taghi Manshouri, Nada Orsolic, Hatice Duzkale, Mary Johansen, Emil J. Freireich, Hagop Kantarjian, Ralph A. Zingaro, Srdan VerstovsekAbstract:Arsenic trioxide (ATO) is an inorganic Arsenic Derivative that is highly effective against PML-RARα -positive leukemia but much less against other hematological malignancies. We synthesized an organic Arsenic Derivative (OAD), S-dimethylarsino-thiosuccinic acid (MER1), which offers a superior toxicity profile and comparable in vitro activity relative to ATO. In Swiss Webster mice, maximally-tolerated cumulative dose of MER1 when given IV for 5 days was 100 mg/kg/d. We demonstrated that MER1 induced apoptosis and dose- and time-dependent inhibition of survival and growth in a panel of myeloid leukemia cell lines. Unlike ATO, this activity was independent of PML-RARα status and was not associated with induction of myeloid maturation. In NB4 and HL60 cells, MER1 and ATO induced caspase activation and dissipation of mitochondrial transmembrane potential. At the same time, MER1 induced generation of reactive oxygen species (ROS) and cell cycle arrest in G2/M phase and proved to be more potent than ATO at inducing apoptosis. ROS generation and intracellular glutathione levels were key modulators of MER1-induced cytotoxicity as evidenced by abrogation of apoptosis in myeloid leukemia cell lines pretreated with the disulfide bond-reducing agent dithiothreitol or the radical scavenger N-acetyl-L-cysteine. Collectively, these data indicate that MER1 induces apoptosis in PML-RARα -positive and -negative myeloid leukemia cells by enhancing oxidative stress. This agent, therefore, combines low in vivo toxicity with formidable in vitro pro-apoptotic ROS-mediated activity, and may represent a novel OAD suitable for clinical development against a variety of hematological malignancies.
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Chemical and clinical development of darinaparsin, a novel organic Arsenic Derivative.
Anti-cancer agents in medicinal chemistry, 2008Co-Authors: Alfonso Quintás-cardama, Srdan Verstovsek, Emil Freireich, Hagop M. Kantarjian, Yiwen Chen, Ralph A. ZingaroAbstract:The inorganic Arsenic Derivative Arsenic trioxide (ATO) has proven to be highly efficacious in patients with acute promyelocytic leukemia (APL) and has been associated with complete cytogenetic response in most treated patients diagnosed with this disease. This is due to ATOs direct effect on PML-RARα oncoprotein patognomonic for APL. ATO has shown moderate activity against certain other hematologic and solid organ malignancies but is also associated with significant toxicities, especially when used at higher doses. The development of orally bioavailable organic Arsenic Derivatives (OAD) offering improved toxicity profiles and better efficacy may expand the use of Arsenic Derivatives in hematologic malignancies and solid tumors. The favorable in vivo carcinostatic activity of S-dimethylarsino-thioglucose, the first OAD synthesized in murine leukemia models by our group in 1975, set the stage for our efforts to develop OADs. Unfortunately, the program remained dormant for almost two decades. The success of ATO in APL in the late 1990s re-ignited the interest in the use of OADs in cancer chemotherapy. This review describes the chemical development of OADs and summarizes the clinical development of a promising lead compound, Darinaparsin (ZIO-101; SGLU; S-dimethylarsino-glutathione), for the treatment of a variety of cancers.