The Experts below are selected from a list of 7881 Experts worldwide ranked by ideXlab platform
Ke Dong - One of the best experts on this subject based on the ideXlab platform.
-
discovery of a novel series of tricyclic oxadiazine 4a methyl esters based on indoxacarb as potential Sodium Channel Blocker modulator insecticides
Journal of Agricultural and Food Chemistry, 2019Co-Authors: Jianqiang Zhang, Wenbo Hao, Ke Dong, Boris S Zhorov, Dingxin JiangAbstract:Indoxacarb, a commercialized oxadiazine insecticide, nearly irreversibly blocks open/inactivated, but not resting Sodium Channels. The structure-activity relationships showed that the substituents at the position of the chiral atom in the oxadiazine ring are very important to the biological activity of oxadiazine insecticide. Here we synthesized a series of tricyclic oxadiazine 4a-methyl ester derivatives. The chiral atom in the oxadiazine ring has been epimerized and substituted with either pyrethric acid or cinnamic acid derivatives. Benzene ring in the tricyclic moiety was substituted with a chlorine, fluorine, or bromine atom, and nitrogen-linked benzene ring was substituted with a trifluoromethyl or trifluoromethoxy group. Toxicity of these compounds against Spodoptera litura F. was evaluated. Diastereoisomers of most toxic compounds J7 and J9 with pyrethric acid moiety were separated by flash column chromatography. The more polar diastereoisomers, J7-L-Rf and J9-L-Rf, and compounds J24 and J26 with cinnamic acid moiety exhibited highest insecticidal activities. We further used Monte Carlo energy minimizations to dock compound J7 and J24 in the NavMs-based homology model of the open cockroach Sodium Channel. In the low-energy binding modes, the compound interacted with residues in the inner pore and domain interfaces, which previously were proposed to contribute to receptors of pyrethroids and Sodium Channel Blocker insecticides. Our results define compound J7 and J24 as a potentially useful optimized hit for the development of multiple sites Sodium Channel Blocker or modulator.
-
The Receptor Site and Mechanism of Action of Sodium Channel Blocker Insecticides
Journal of Biological Chemistry, 2016Co-Authors: Yongqiang Zhang, Dingxin Jiang, Yoshiko Nomura, Boris S Zhorov, Caitlyn Behnke, Ke DongAbstract:Sodium Channels are excellent targets of both natural and synthetic insecticides with high insect selectivity. Indoxacarb, its active metabolite DCJW, and metaflumizone (MFZ) belong to a relatively new class of Sodium Channel Blocker insecticides (SCBIs) with a mode of action distinct from all other Sodium Channel-targeting insecticides, including pyrethroids. Electroneutral SCBIs preferably bind to and trap Sodium Channels in the inactivated state, a mechanism similar to that of cationic local anesthetics. Previous studies identified several SCBI-sensing residues that face the inner pore of Sodium Channels. However, the receptor site of SCBIs, their atomic mechanisms, and the cause of selective toxicity of MFZ remain elusive. Here, we have built a homology model of the open-state cockroach Sodium Channel BgNav1-1a. Our computations predicted that SCBIs bind in the inner pore, interact with a Sodium ion at the focus of P1 helices, and extend their aromatic moiety into the III/IV domain interface (fenestration). Using model-driven mutagenesis and electrophysiology, we identified five new SCBI-sensing residues, including insect-specific residues. Our study proposes the first three-dimensional models of Channel-bound SCBIs, sheds light on the molecular basis of MFZ selective toxicity, and suggests that a Sodium ion located in the inner pore contributes to the receptor site for electroneutral SCBIs.
-
mutations in the transmembrane helix s6 of domain iv confer cockroach Sodium Channel resistance to Sodium Channel Blocker insecticides and local anesthetics
Insect Biochemistry and Molecular Biology, 2015Co-Authors: Dingxin Jiang, Yoshiko Nomura, Boris S Zhorov, Xingliang Wang, Ke DongAbstract:Indoxacarb and metaflumizone are two Sodium Channel Blocker insecticides (SCBIs). They preferably bind to and trap Sodium Channels in the slow-inactivated non-conducting state, a mode of action similar to that of local anesthetics (LAs). Recently, two Sodium Channel mutations, F1845Y (F(4i15)Y) and V1848I (V(4i18)I), in the transmembrane segment 6 of domain IV (IVS6), were identified to be associated with indoxacarb resistance in Plutella xylostella. F(4i15) is known to be critical for the action of LAs on mammalian Sodium Channels. Previously, mutation F(4i15)A in a cockroach Sodium Channel, BgNav1-1a, has been shown to reduce the action of lidocaine, a LA, but not the action of SCBIs. In this study, we introduced mutations F(4i15)Y and V(4i18)A/I individually into the cockroach Sodium Channel, BgNav1-1a, and conducted functional analysis of the three mutants in Xenopus oocytes. We found that both the F(4i15)Y and V(4i18)I mutations reduced the inhibition of Sodium current by indoxacarb, DCJW (an active metabolite of indoxacarb) and metaflumizone. F(4i15)Y and V(4i18)I mutations also reduced the use-dependent block of Sodium current by lidocaine. In contrast, substitution V(4i18)A enhanced the action metaflumizone and lidocaine. These results show that both F(4i15)Y and V(4i18)I mutations may contribute to target-site resistance to SCBIs, and provide the first molecular evidence for common amino acid determinants on insect Sodium Channels involved in action of SCBIs and LA.
-
Mechanism of action of Sodium Channel Blocker insecticides (SCBIs) on insect Sodium Channels.
Pesticide Biochemistry and Physiology, 2010Co-Authors: Kristopher Silver, Weizhong Song, Yoshiko Nomura, Vincent L. Salgado, Ke DongAbstract:Sodium Channel Blocker insecticides (SCBIs) are a relatively new class of insecticides, with a mechanism of action different from those of other classes of insecticides that target voltage-gated Sodium Channels. These compounds have no effect at hyperpolarized membrane potentials, but cause a voltage-dependent, nearly irreversible block as the membrane potential is depolarized. The mechanism of action of SCBIs is similar to that of local anesthetics (LAs), class I anticonvulsants and class I antiarrhythmics. In this article, we review the physiological actions of these compounds on the whole animal, the nervous system and Sodium Channels, and also present the results from recent studies that elucidate the receptor site of SCBIs.
-
role of the sixth transmembrane segment of domain iv of the cockroach Sodium Channel in the action of Sodium Channel Blocker insecticides
Neurotoxicology, 2009Co-Authors: Kristopher Silver, Yoshiko Nomura, Vincent L. Salgado, Ke DongAbstract:Sodium Channel Blocker insecticides (SCBIs), such as indoxacarb and metaflumizone, are a new class of insecticides with a mechanism of action different from those of other insecticides that target Sodium Channels. SCBIs block Sodium Channels in a manner similar to local anesthetics (LAs) such as lidocaine. Several residues, particularly F1579 and Y1586, in the sixth transmembrane segment (S6) of domain IV (IV) of rat Nav1.4 Sodium Channels are required for the action of LAs and SCBIs and may form part of overlapping receptor sites. However, the binding site for SCBIs in insect Sodium Channels remains undefined. We used site-directed mutagenesis, the Xenopus laevis oocyte expression system, and the two-electrode voltage clamp technique to study the effects on SCBI activity of mutating F1817 and Y1824 (analogous to those residues identified in mammalian Sodium Channels) to alanine, in the voltage-sensitive Sodium Channel of the German cockroach, Blattella germanica. The mutant Channels showed no effect or a marked increase in Channel sensitivity to both DCJW (the active metabolite of indoxacarb) and metaflumizone. Thus, it appeared that although the F1817 residue plays a role in the action of SCBIs and that both residues are involved in LA activity in mammalian Sodium Channels, neither F1817 nor Y1824 are integral determinants of SCBI binding on insect Sodium Channels. Our results suggest that the receptor site of SCBIs on insect Sodium Channels may be significantly different from that on mammalian Sodium Channels.
Dingxin Jiang - One of the best experts on this subject based on the ideXlab platform.
-
discovery of a novel series of tricyclic oxadiazine 4a methyl esters based on indoxacarb as potential Sodium Channel Blocker modulator insecticides
Journal of Agricultural and Food Chemistry, 2019Co-Authors: Jianqiang Zhang, Wenbo Hao, Ke Dong, Boris S Zhorov, Dingxin JiangAbstract:Indoxacarb, a commercialized oxadiazine insecticide, nearly irreversibly blocks open/inactivated, but not resting Sodium Channels. The structure-activity relationships showed that the substituents at the position of the chiral atom in the oxadiazine ring are very important to the biological activity of oxadiazine insecticide. Here we synthesized a series of tricyclic oxadiazine 4a-methyl ester derivatives. The chiral atom in the oxadiazine ring has been epimerized and substituted with either pyrethric acid or cinnamic acid derivatives. Benzene ring in the tricyclic moiety was substituted with a chlorine, fluorine, or bromine atom, and nitrogen-linked benzene ring was substituted with a trifluoromethyl or trifluoromethoxy group. Toxicity of these compounds against Spodoptera litura F. was evaluated. Diastereoisomers of most toxic compounds J7 and J9 with pyrethric acid moiety were separated by flash column chromatography. The more polar diastereoisomers, J7-L-Rf and J9-L-Rf, and compounds J24 and J26 with cinnamic acid moiety exhibited highest insecticidal activities. We further used Monte Carlo energy minimizations to dock compound J7 and J24 in the NavMs-based homology model of the open cockroach Sodium Channel. In the low-energy binding modes, the compound interacted with residues in the inner pore and domain interfaces, which previously were proposed to contribute to receptors of pyrethroids and Sodium Channel Blocker insecticides. Our results define compound J7 and J24 as a potentially useful optimized hit for the development of multiple sites Sodium Channel Blocker or modulator.
-
The Receptor Site and Mechanism of Action of Sodium Channel Blocker Insecticides
Journal of Biological Chemistry, 2016Co-Authors: Yongqiang Zhang, Dingxin Jiang, Yoshiko Nomura, Boris S Zhorov, Caitlyn Behnke, Ke DongAbstract:Sodium Channels are excellent targets of both natural and synthetic insecticides with high insect selectivity. Indoxacarb, its active metabolite DCJW, and metaflumizone (MFZ) belong to a relatively new class of Sodium Channel Blocker insecticides (SCBIs) with a mode of action distinct from all other Sodium Channel-targeting insecticides, including pyrethroids. Electroneutral SCBIs preferably bind to and trap Sodium Channels in the inactivated state, a mechanism similar to that of cationic local anesthetics. Previous studies identified several SCBI-sensing residues that face the inner pore of Sodium Channels. However, the receptor site of SCBIs, their atomic mechanisms, and the cause of selective toxicity of MFZ remain elusive. Here, we have built a homology model of the open-state cockroach Sodium Channel BgNav1-1a. Our computations predicted that SCBIs bind in the inner pore, interact with a Sodium ion at the focus of P1 helices, and extend their aromatic moiety into the III/IV domain interface (fenestration). Using model-driven mutagenesis and electrophysiology, we identified five new SCBI-sensing residues, including insect-specific residues. Our study proposes the first three-dimensional models of Channel-bound SCBIs, sheds light on the molecular basis of MFZ selective toxicity, and suggests that a Sodium ion located in the inner pore contributes to the receptor site for electroneutral SCBIs.
-
mutations in the transmembrane helix s6 of domain iv confer cockroach Sodium Channel resistance to Sodium Channel Blocker insecticides and local anesthetics
Insect Biochemistry and Molecular Biology, 2015Co-Authors: Dingxin Jiang, Yoshiko Nomura, Boris S Zhorov, Xingliang Wang, Ke DongAbstract:Indoxacarb and metaflumizone are two Sodium Channel Blocker insecticides (SCBIs). They preferably bind to and trap Sodium Channels in the slow-inactivated non-conducting state, a mode of action similar to that of local anesthetics (LAs). Recently, two Sodium Channel mutations, F1845Y (F(4i15)Y) and V1848I (V(4i18)I), in the transmembrane segment 6 of domain IV (IVS6), were identified to be associated with indoxacarb resistance in Plutella xylostella. F(4i15) is known to be critical for the action of LAs on mammalian Sodium Channels. Previously, mutation F(4i15)A in a cockroach Sodium Channel, BgNav1-1a, has been shown to reduce the action of lidocaine, a LA, but not the action of SCBIs. In this study, we introduced mutations F(4i15)Y and V(4i18)A/I individually into the cockroach Sodium Channel, BgNav1-1a, and conducted functional analysis of the three mutants in Xenopus oocytes. We found that both the F(4i15)Y and V(4i18)I mutations reduced the inhibition of Sodium current by indoxacarb, DCJW (an active metabolite of indoxacarb) and metaflumizone. F(4i15)Y and V(4i18)I mutations also reduced the use-dependent block of Sodium current by lidocaine. In contrast, substitution V(4i18)A enhanced the action metaflumizone and lidocaine. These results show that both F(4i15)Y and V(4i18)I mutations may contribute to target-site resistance to SCBIs, and provide the first molecular evidence for common amino acid determinants on insect Sodium Channels involved in action of SCBIs and LA.
-
Design, synthesis and structure-activity relationship of indoxacarb analogs as voltage-gated Sodium Channel Blocker.
Bioorganic & Medicinal Chemistry Letters, 2015Co-Authors: Wenbo Hao, Chen Jian, Guang Shao, Dingxin JiangAbstract:Indoxacarb, the first commercialized pyrazoline-type Sodium-Channel Blocker, is a commonly used insecticide because of high selectivity. To discover Sodium-Channel Blocker with high insecticidal activity, a series of novel indoxacarb analogs were designed and synthesized by judicious structural modifications of the substituent group of C5, C6 in indenone and C'4 in benzene ring. Some analogs exhibited significant insecticidal activities against Spodoptera litura F. and excellent BgNav1-1a Channel inhibitory activity. The structure-activity analysis indicated that the presence of strong electron-withdrawing group and decreased steric hindrance of indenone ring (R(1), R(2)) in 5- and 6-position could enhance larvicidal activity and BgNav1-1a Channel inhibitory activity.
John N D Wurpel - One of the best experts on this subject based on the ideXlab platform.
-
a 803467 a tetrodotoxin resistant Sodium Channel Blocker modulates abcg2 mediated mdr in vitro and in vivo
Oncotarget, 2015Co-Authors: Nagaraju Anreddy, Priyank Kumar, Atish Patel, Yunkai Zhang, Yijun Wang, Rishil J Kathawala, Suneet Shukla, Pranav Gupta, Suresh V Ambudkar, John N D WurpelAbstract:// Nagaraju Anreddy 1, * , Atish Patel 1 , Yun-Kai Zhang 1 , Yi-Jun Wang 1 , Suneet Shukla 2 , Rishil J. Kathawala 1 , Priyank Kumar 1 , Pranav Gupta 1 , Suresh V. Ambudkar 2 , John N. D. Wurpel 1 , Zhe-Sheng Chen 1 , Huiqin Guo 3, * 1 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA 2 Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA 3 Department of Thoracic Surgery, Peking Union Medical College Hospital, Beijing 100730, P.R. China * These authors have contributed equally to this work Correspondence to: Huiqin Guo, e-mail: guohuiqin2@163.com Zhe-Sheng Chen, e-mail: chenz@stjohns.edu Keywords: multidrug resistance, ABCG2, ABC transporters, non-small cell lung cancer Received: July 22, 2015 Accepted: October 09, 2015 Published: October 22, 2015 ABSTRACT ATP-binding cassette subfamily G member 2 (ABCG2) is a member of the ABC transporter superfamily proteins, which has been implicated in the development of multidrug resistance (MDR) in cancer, apart from its physiological role to remove toxic substances out of the cells. The diverse range of substrates of ABCG2 includes many antineoplastic agents such as topotecan, doxorubicin and mitoxantrone. ABCG2 expression has been reported to be significantly increased in some solid tumors and hematologic malignancies, correlated to poor clinical outcomes. In addition, ABCG2 expression is a distinguishing feature of cancer stem cells, whereby this membrane transporter facilitates resistance to the chemotherapeutic drugs. To enhance the chemosensitivity of cancer cells, attention has been focused on MDR modulators. In this study, we investigated the effect of a tetrodotoxin-resistant Sodium Channel Blocker, A-803467 on ABCG2-overexpressing drug selected and transfected cell lines. We found that at non-toxic concentrations, A-803467 could significantly increase the cellular sensitivity to ABCG2 substrates in drug-resistant cells overexpressing either wild-type or mutant ABCG2. Mechanistic studies demonstrated that A-803467 (7.5 μM) significantly increased the intracellular accumulation of [ 3 H]-mitoxantrone by inhibiting the transport activity of ABCG2, without altering its expression levels. In addition, A-803467 stimulated the ATPase activity in membranes overexpressed with ABCG2. In a murine model system, combination treatment of A-803467 (35 mg/kg) and topotecan (3 mg/kg) significantly inhibited the tumor growth in mice xenografted with ABCG2-overexpressing cancer cells. Our findings indicate that a combination of A-803467 and ABCG2 substrates may potentially be a novel therapeutic treatment in ABCG2-positive drug resistant cancers.
-
abstract 4432 a 803467 a tetrodotoxin resistant Sodium Channel Blocker modulates abcg2 mediated mdr in vitro and in vivo
Cancer Research, 2015Co-Authors: Nagaraju Anreddy, Priyank Kumar, Atish Patel, Yunkai Zhang, Yijun Wang, Rishil J Kathawala, Suneet Shukla, Pranav Gupta, Suresh V Ambudkar, John N D WurpelAbstract:ABCG2 is a member of the ABC transporter superfamily, which has been implicated in the development of multidrug resistance (MDR) in cancer. Its diverse range of substrates includes many antineoplastic agents such as topotecan, doxorubicin and mitoxantrone. ABCG2 expression has been significantly increased in some solid tumors and hematologic malignancies, which is correlated to poorer clinical outcomes. In addition, ABCG2 expression is a distinguishing feature of cancer stem cells, whereby this membrane transporter impacts resistance to the chemotherapeutic drugs. To enhance the chemosensitivity of cancer cells, attention has been focused on MDR modulators. In this study, we investigated the ability of a tetrodotoxin-resistant Sodium Channel Blocker, A-803467 to reverse ABCG2-mediated MDR. We found that A-803467 at non-toxic concentration could significantly increase the cellular sensitivity to ABCG2 substrates in drug-resistant cells overexpressing either wild-type or mutant ABCG2. Mechanistic studies indicated that A-803467 (7.5 μM) significantly increased the intracellular accumulation of mitoxantrone by inhibiting the transport activity of ABCG2, without altering its expression level. In addition, A-803467 stimulated the ATPase activity of ABCG2 in a concentration-dependent manner, indicating that A-803467 might be a substrate of ABCG2. Binding interactions of A-803467 were found to be in transmembrane region of homology modeled human ABCG2. Interactions of A-803467 with ABCG2 were relatively stronger when compared to the interactions of topotecan with ABCG2. Furthermore, A-803467 (30 mg/kg) with topotecan (3 mg/kg) significantly decreased the growth rate and tumor size of ABCG2 overexpressing tumors in a xenograft nude mouse model. Our findings indicate that A-803467 has the potential to be used in combination with ABCG2 chemotherapeutic substrates to improve the response in drug resistant cancers. Citation Format: Nagaraju Anreddy, Atish Patel, Yun-Kai Zhang, Yi-Jun Wang, Suneet Shukla, Rishil J. Kathawala, Priyank Kumar, Pranav Gupta, Suresh V. Ambudkar, John ND Wurpel, Zhe-Sheng Chen. A-803467, a tetrodotoxin-resistant Sodium Channel Blocker, modulates ABCG2-mediated MDR in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4432. doi:10.1158/1538-7445.AM2015-4432
-
abstract a01 a 803467 a Sodium Channel Blocker reverses abcg2 mediated mdr in vitro as well as in vivo
Clinical Cancer Research, 2015Co-Authors: Nagaraju Anreddy, Priyank Kumar, Atish Patel, Yunkai Zhang, Yijun Wang, Rishil J Kathawala, John N D Wurpel, Zhesheng ChenAbstract:The ATP-binding cassette, subfamily G, isoform 2 protein (ABCG2) is a vital member of the ABC transporter superfamily, which has been involved in multidrug resistance (MDR) in cancer. Its diverse range of substrates includes many antineoplastic agents such as doxorubicin and mitoxantrone. ABCG2 expression has been significantly increased in some solid tumors and hematologic malignancies, which is correlated to poorer clinical outcomes. In addition, ABCG2 expression is a distinguishing feature of cancer stem cells, whereby this membranous transporter imparts resistance to the chemotherapeutic drugs. To enhance the chemosensitivity of cancer cells, attention has been focused on MDR modulators. In this study, we investigated the ability of Sodium Channel Blocker, A-803467 to reverse ABCG2-mediated MDR. We found that A-803467 at non-toxic concentration could significantly increase the cellular sensitivity to ABCG2 substrates in drug-resistant cells overexpressing either wild-type or mutant ABCG2. Mechanistic studies indicated that A-803467 (7.5 μM) significantly increased the intracellular accumulation resulted from inhibition of the efflux of mitoxantrone by inhibiting the transport activity without altering expression level of ABCG2 protein. Furthermore, ATPase analysis indicates that A-803467 stimulates the ATPase activity in membranes overexpressing ABCG2. in-vivo results indicating that tumor volume was significantly decreased by combination of A-803467 with topotecan when compared to the topotecan and A-803467 alone group. Our findings suggest that A-803467 has the potential to be used in combination with ABCG2 chemotherapeutic substrates to augment the response in drug resistant cancers. Citation Format: Nagaraju Anreddy, Priyank Kumar, Atish Patel, Yun-Kai Zhang, Yijun Wang, Rishil Kathawala, John D. Wurpel, Zhe-Sheng Chen. A-803467, a Sodium Channel Blocker, reverses ABCG2-mediated MDR in vitro as well as in vivo. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A01.
Nagaraju Anreddy - One of the best experts on this subject based on the ideXlab platform.
-
a 803467 a tetrodotoxin resistant Sodium Channel Blocker modulates abcg2 mediated mdr in vitro and in vivo
Oncotarget, 2015Co-Authors: Nagaraju Anreddy, Priyank Kumar, Atish Patel, Yunkai Zhang, Yijun Wang, Rishil J Kathawala, Suneet Shukla, Pranav Gupta, Suresh V Ambudkar, John N D WurpelAbstract:// Nagaraju Anreddy 1, * , Atish Patel 1 , Yun-Kai Zhang 1 , Yi-Jun Wang 1 , Suneet Shukla 2 , Rishil J. Kathawala 1 , Priyank Kumar 1 , Pranav Gupta 1 , Suresh V. Ambudkar 2 , John N. D. Wurpel 1 , Zhe-Sheng Chen 1 , Huiqin Guo 3, * 1 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA 2 Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA 3 Department of Thoracic Surgery, Peking Union Medical College Hospital, Beijing 100730, P.R. China * These authors have contributed equally to this work Correspondence to: Huiqin Guo, e-mail: guohuiqin2@163.com Zhe-Sheng Chen, e-mail: chenz@stjohns.edu Keywords: multidrug resistance, ABCG2, ABC transporters, non-small cell lung cancer Received: July 22, 2015 Accepted: October 09, 2015 Published: October 22, 2015 ABSTRACT ATP-binding cassette subfamily G member 2 (ABCG2) is a member of the ABC transporter superfamily proteins, which has been implicated in the development of multidrug resistance (MDR) in cancer, apart from its physiological role to remove toxic substances out of the cells. The diverse range of substrates of ABCG2 includes many antineoplastic agents such as topotecan, doxorubicin and mitoxantrone. ABCG2 expression has been reported to be significantly increased in some solid tumors and hematologic malignancies, correlated to poor clinical outcomes. In addition, ABCG2 expression is a distinguishing feature of cancer stem cells, whereby this membrane transporter facilitates resistance to the chemotherapeutic drugs. To enhance the chemosensitivity of cancer cells, attention has been focused on MDR modulators. In this study, we investigated the effect of a tetrodotoxin-resistant Sodium Channel Blocker, A-803467 on ABCG2-overexpressing drug selected and transfected cell lines. We found that at non-toxic concentrations, A-803467 could significantly increase the cellular sensitivity to ABCG2 substrates in drug-resistant cells overexpressing either wild-type or mutant ABCG2. Mechanistic studies demonstrated that A-803467 (7.5 μM) significantly increased the intracellular accumulation of [ 3 H]-mitoxantrone by inhibiting the transport activity of ABCG2, without altering its expression levels. In addition, A-803467 stimulated the ATPase activity in membranes overexpressed with ABCG2. In a murine model system, combination treatment of A-803467 (35 mg/kg) and topotecan (3 mg/kg) significantly inhibited the tumor growth in mice xenografted with ABCG2-overexpressing cancer cells. Our findings indicate that a combination of A-803467 and ABCG2 substrates may potentially be a novel therapeutic treatment in ABCG2-positive drug resistant cancers.
-
abstract 4432 a 803467 a tetrodotoxin resistant Sodium Channel Blocker modulates abcg2 mediated mdr in vitro and in vivo
Cancer Research, 2015Co-Authors: Nagaraju Anreddy, Priyank Kumar, Atish Patel, Yunkai Zhang, Yijun Wang, Rishil J Kathawala, Suneet Shukla, Pranav Gupta, Suresh V Ambudkar, John N D WurpelAbstract:ABCG2 is a member of the ABC transporter superfamily, which has been implicated in the development of multidrug resistance (MDR) in cancer. Its diverse range of substrates includes many antineoplastic agents such as topotecan, doxorubicin and mitoxantrone. ABCG2 expression has been significantly increased in some solid tumors and hematologic malignancies, which is correlated to poorer clinical outcomes. In addition, ABCG2 expression is a distinguishing feature of cancer stem cells, whereby this membrane transporter impacts resistance to the chemotherapeutic drugs. To enhance the chemosensitivity of cancer cells, attention has been focused on MDR modulators. In this study, we investigated the ability of a tetrodotoxin-resistant Sodium Channel Blocker, A-803467 to reverse ABCG2-mediated MDR. We found that A-803467 at non-toxic concentration could significantly increase the cellular sensitivity to ABCG2 substrates in drug-resistant cells overexpressing either wild-type or mutant ABCG2. Mechanistic studies indicated that A-803467 (7.5 μM) significantly increased the intracellular accumulation of mitoxantrone by inhibiting the transport activity of ABCG2, without altering its expression level. In addition, A-803467 stimulated the ATPase activity of ABCG2 in a concentration-dependent manner, indicating that A-803467 might be a substrate of ABCG2. Binding interactions of A-803467 were found to be in transmembrane region of homology modeled human ABCG2. Interactions of A-803467 with ABCG2 were relatively stronger when compared to the interactions of topotecan with ABCG2. Furthermore, A-803467 (30 mg/kg) with topotecan (3 mg/kg) significantly decreased the growth rate and tumor size of ABCG2 overexpressing tumors in a xenograft nude mouse model. Our findings indicate that A-803467 has the potential to be used in combination with ABCG2 chemotherapeutic substrates to improve the response in drug resistant cancers. Citation Format: Nagaraju Anreddy, Atish Patel, Yun-Kai Zhang, Yi-Jun Wang, Suneet Shukla, Rishil J. Kathawala, Priyank Kumar, Pranav Gupta, Suresh V. Ambudkar, John ND Wurpel, Zhe-Sheng Chen. A-803467, a tetrodotoxin-resistant Sodium Channel Blocker, modulates ABCG2-mediated MDR in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4432. doi:10.1158/1538-7445.AM2015-4432
-
abstract a01 a 803467 a Sodium Channel Blocker reverses abcg2 mediated mdr in vitro as well as in vivo
Clinical Cancer Research, 2015Co-Authors: Nagaraju Anreddy, Priyank Kumar, Atish Patel, Yunkai Zhang, Yijun Wang, Rishil J Kathawala, John N D Wurpel, Zhesheng ChenAbstract:The ATP-binding cassette, subfamily G, isoform 2 protein (ABCG2) is a vital member of the ABC transporter superfamily, which has been involved in multidrug resistance (MDR) in cancer. Its diverse range of substrates includes many antineoplastic agents such as doxorubicin and mitoxantrone. ABCG2 expression has been significantly increased in some solid tumors and hematologic malignancies, which is correlated to poorer clinical outcomes. In addition, ABCG2 expression is a distinguishing feature of cancer stem cells, whereby this membranous transporter imparts resistance to the chemotherapeutic drugs. To enhance the chemosensitivity of cancer cells, attention has been focused on MDR modulators. In this study, we investigated the ability of Sodium Channel Blocker, A-803467 to reverse ABCG2-mediated MDR. We found that A-803467 at non-toxic concentration could significantly increase the cellular sensitivity to ABCG2 substrates in drug-resistant cells overexpressing either wild-type or mutant ABCG2. Mechanistic studies indicated that A-803467 (7.5 μM) significantly increased the intracellular accumulation resulted from inhibition of the efflux of mitoxantrone by inhibiting the transport activity without altering expression level of ABCG2 protein. Furthermore, ATPase analysis indicates that A-803467 stimulates the ATPase activity in membranes overexpressing ABCG2. in-vivo results indicating that tumor volume was significantly decreased by combination of A-803467 with topotecan when compared to the topotecan and A-803467 alone group. Our findings suggest that A-803467 has the potential to be used in combination with ABCG2 chemotherapeutic substrates to augment the response in drug resistant cancers. Citation Format: Nagaraju Anreddy, Priyank Kumar, Atish Patel, Yun-Kai Zhang, Yijun Wang, Rishil Kathawala, John D. Wurpel, Zhe-Sheng Chen. A-803467, a Sodium Channel Blocker, reverses ABCG2-mediated MDR in vitro as well as in vivo. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A01.
-
Abstract 1967: A-803467, a Sodium Channel Blocker, reverses ABCG2-mediated MDR
Tumor Biology, 2014Co-Authors: Nagaraju AnreddyAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The ATP-binding cassette, subfamily G, isoform 2 protein (ABCG2) is a vital member of the ABC transporter superfamily, which has been involved in multidrug resistance (MDR) in cancer. Its diverse range of substrates includes many antineoplastic agents such as doxorubicin and mitoxantrone. ABCG2 expression has been significantly increased in some solid tumors and hematologic malignancies, which is correlated to poorer clinical outcomes. In addition, ABCG2 expression is a distinguishing feature of cancer stem cells, whereby this membranous transporter imparts resistance to the chemotherapeutic drugs. To enhance the chemosensitivity of cancer cells, attention has been focused on MDR modulators. In this study, we investigated the ability of Sodium Channel Blocker, A-803467 to reverse ABCG2-mediated MDR. We found that A-803467 at non-toxic concentration could significantly increase the cellular sensitivity to ABCG2 substrates in drug-resistant cells overexpressing either wild-type or mutant ABCG2. Mechanistic studies indicated that A-803467 (7.5 μM) significantly increased the intracellular accumulation resulted from inhibition of the efflux of mitoxantrone by inhibiting the transport activity without altering expression level of ABCG2 protein. Furthermore, ATPase analysis indicates that A-803467 stimulates the ATPase activity in membranes overexpressing ABCG2. Our findings suggest that A-803467 has the potential to be used in combination with ABCG2 chemotherapeutic substrates to augment the response in drug resistant cancers. Citation Format: Nagaraju Anreddy. A-803467, a Sodium Channel Blocker, reverses ABCG2-mediated MDR. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1967. doi:10.1158/1538-7445.AM2014-1967
Joanne Palmer - One of the best experts on this subject based on the ideXlab platform.
-
Discovery of Vixotrigine: A Novel Use-Dependent Sodium Channel Blocker for the Treatment of Trigeminal Neuralgia.
ACS Medicinal Chemistry Letters, 2020Co-Authors: David R Witty, Giuseppe Alvaro, Dominique Derjean, Gerard M P Giblin, Kevin Gunn, Charles Large, David T Macpherson, Valerie Morisset, Davina Owen, Joanne PalmerAbstract:Drugs that block voltage-gated Sodium Channels (NaVs) have utility in treating conditions including pain, epilepsy, and cardiac arrhythmias and as anesthetics (Lancet Neurol.20109413424; Expert Opin. Ther. Pat.201020755779). The identification of compounds with improved efficacy and safety is a key aim for the discovery of improved NaV blocking drugs (Comprehensive Medicinal Chemistry III; (Elsevier, 2017; pp 131-175). We report the identification of a novel class of brain penetrant and voltage-gated Sodium Channel Blockers, leading to the discovery of vixotrigine, a use-dependent Sodium Channel Blocker with activity in in vivo models of pain. Vixotrigine has excellent physiocochemical properties for drug development, and both preclinical and clinical data support a safety profile suitable for potential use in neuropathic pain and other conditions. It has shown efficacy in a Phase II study for pain associated with trigeminal neuralgia.
-
safety and efficacy of a nav1 7 selective Sodium Channel Blocker in patients with trigeminal neuralgia a double blind placebo controlled randomised withdrawal phase 2a trial
Lancet Neurology, 2017Co-Authors: Joanna M Zakrzewska, Gerard M P Giblin, Valerie Morisset, Joanne Palmer, Mark Obermann, Dominik A Ettlin, G Cruccu, Lars Bendtsen, Mark Estacion, Dominique DerjeanAbstract:Summary Background Current standard of care for trigeminal neuralgia is treatment with the Sodium Channel Blockers carbamazepine and oxcarbazepine, which although effective are associated with poor tolerability and the need for titration. BIIB074, a Nav1.7-selective, state-dependent Sodium-Channel Blocker, can be administered at therapeutic doses without titration, and has shown good tolerability in healthy individuals in phase 1 studies. We therefore assessed the safety and efficacy of BIIB074 in patients with trigeminal neuralgia in a phase 2a study. Methods We did a double-blind, multicentre, placebo-controlled, randomised withdrawal phase 2a trial in 25 secondary care centres in Denmark, Estonia, France, Germany, Italy, Latvia, Lithuania, Romania, South Africa, Spain, Switzerland, and the UK. After a 7-day run-in phase, eligible patients aged 18–80 years with confirmed trigeminal neuralgia received open-label, BIIB074 150 mg three times per day, orally, for 21 days. Patients who met at least one response criteria were then randomly assigned (1:1) to BIIB074 or placebo for up to 28 days in a double-blind phase. We used an interactive web response system to assign patients with a computer-generated schedule, with stratification (presence or absence of existing pain medication). Patients, clinicians, and assessors were masked to treatment allocation. The primary endpoint was the difference between groups in the number of patients classified as treatment failure during the double blind phase assessed in the modified intention-to-treat population. We assessed safety in all patients who received one or more doses of BIIB074. This study is registered with ClinicalTrials.gov (NCT01540630) and EudraCT (2010-023963-16). Findings The first patient was enrolled on April 23, 2012, and the last patient completed the study on February 26, 2014. We enrolled 67 patients into the open-label phase; 44 completed open-label treatment, and 29 were randomly assigned to double-blind treatment (15 to BIIB074 and 14 to placebo). During the double-blind phase, five (33%) patients assigned to BIIB074 versus nine (64%) assigned to placebo were classified as treatment failures (p=0·0974). BIIB074 was well tolerated, with similar adverse events in the double-blind phase to placebo. Headache was the most common adverse event with BIIB074 in the open-label phase (in 13 [19%] of 67 patients), followed by dizziness (in six [9%] patients). In the double-blind phase, headache, pyrexia, nasopharyngitis, sleep disorder, and tremor were the most frequent adverse events in patients assigned to BIIB074 (in one [7%] of 15 patients for each event), and headache, dizziness, diarrhoea, and vomiting were the most frequent adverse events in patients assigned to placebo (in one [7%] of 14 patients for each event). No severe or serious adverse events were reported in the BIIB074 group during the double-blind phase. One patient assigned to placebo reported intestinal adhesions with obstruction as a severe and serious adverse event, which was considered as unrelated to study medication. Interpretation The primary endpoint of treatment failure was not significantly lower in the BIIB074 group than in the placebo group. However, our findings provide a basis for continued investigation of BIIB074 in patients with trigeminal neuralgia in future clinical trials. Funding Convergence Pharmaceuticals.