[[abstract]]Purpose: The goal of targeted therapy is to identify the suitable target molecules to... more [[abstract]]Purpose: The goal of targeted therapy is to identify the suitable target molecules to be inhibited, in order to achieve the best antitumor effect. The classical viewpoint is that inhibitor acting on single target allows selectivity and less adverse effect. However, clinical experience revealed that almost relapsed cancer patients developed drug resistance, often due to the activation or development of alternative signaling pathways or mutations that single target drugs are unable to effectively inhibit them. A current trend in the development of kinase inhibitors is the assumption that multi targeted therapy, which targets at several signaling pathways simultaneously, is more effective than single targeted therapy. Thus, paradigm in designing new anticancer drug is shifted: The drugs that act on multiple targets might have a better chance of inhibiting cancer cell proliferation than drugs that act on a single target. The objective of this research is aimed at identifying a multi-targeted kinase inhibitor as a development candidate for cancer therapy. Material and Method: We established Structure–Activity Relationship (S.A.R.) study based on 800 compounds that were synthesized by High Throughput Parallel Synthesis. Scaffold hopping approach by changing pharmacophore moiety had led us to discover DBPR114 as a multiple-targeted kinase inhibitor. Results: We discovered a novel multiple-targeted kinase inhibitor, DBPR114, that effectively inhibited 15 kinases in a panel of 57 oncogenic related kinases profiling, particularly against to Aurora kinase A and B, FLT-1, FLT-3 and c-Met in nanomolar range. In pharmacological study, DBPR114 significantly shrank tumor in 8 different xenograft models including Mia-Paca2, AsPC-1 (pancreatic carcinoma), Hep3B (hepatocellular carcinoma), MKN-45 (gastric carcinoma), MOLM-13 and MV4;11 (acute myeloid leukemia), NTUB-1 (bladder cancer), and Colo-205 (colorectal carcinoma) at a dose of 3 to 20 mg/kg by intravenous administration without significant adverse effect in most group of in vivo evaluations. Conclusion: This multiple targeting inhibitory properties plays a major role to shrinks tumor growth of various cancer cells in vivo and in vivo such as MOLM-13, MV4;11, MKN45, Colo-205, Mia-Paca2 and NTUB-1. The broad spectrum of anti-tumor activity of BPR1K0871 provides a great potential to become a promising multi-targeted kinase inhibitors as next generation of anti-cancer drug
Colon cancer has high incidence rate in the world and the early stage of colon cancer can be cure... more Colon cancer has high incidence rate in the world and the early stage of colon cancer can be cured by surgical therapy. However, it remains difficult to predict the prognostic outcome of colon cancer patients. STK4 is considered as a potential tumor suppressor, which plays an important role in Hippo pathway to control the organ size and the inhibition ability of cell-cell contact. The major aim of this study is focused on the investigation of prognostic value of STK4 in colon cancer. By immunohistochemistry assay, we examined the expression of STK4 in 140 pairs normal and tumor colon cancer specimens. The relationship between STK4 expression and clinicopathological factors as well as patient survival were analyzed and the results showed that STK4 was significantly downregulated in tumor tissues compared to their corresponding non-tumor part (P<0.01) and that was significantly associated with tumor size (P=0.003), distal metastasis (P=0.03), disease recurrence and poor survival (P<0.005). Moreover, loss of STK4 expression showed a significant poor outcome in colon cancer patients by univariate and multivariate analysis. These results indicated that there is a positive correlation in STK4 expression and prognosis and survival of colon cancer patients. Loss of STK4 expression displayed poor outcome. The conclusion is that STK4 can be used as a prognostic maker to predict patient survival and play a role in metastasis suppression of colorectal cancer. Citation Format: Yu-Cheng Lee, Chia-Ning Yang, Tai-I Hsu, Pei-Jung Lu. STK4 downregulation promotes tumor invasion/migration and is associated with poor prognosis in human colon cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1146. doi:10.1158/1538-7445.AM2013-1146
Methadone (Mtd) is a widely used opioid drug associated with the side effect of hyperprolactinemi... more Methadone (Mtd) is a widely used opioid drug associated with the side effect of hyperprolactinemia. The mechanism of how Mtd induces prolactin secretion remains unclear. The effects of Mtd and its two main metabolites (EDDP: (±)-2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium percholarate and EMDP: 2-ethyl-5-methyl-3,3-dipnehyl-1-pyrroline) on ion currents were investigated in GH₃ pituitary tumor cells. Hyperpolarization-elicited K+ currents in GH₃ cells bathed in a high-K(+), Ca(2+)-free solution were studied to evaluate the effects of Mtd and other related compounds on the ether-à-go-go-related-gene (erg) K(+) current (I(K(erg))). Mtd suppressed the amplitude of I(K(erg)) in a concentration-dependent manner with an IC(50) value of 10.4 μM. With the aid of a minimal binding scheme, the inhibitory action of Mtd on I(K(erg)) was estimated with a dissociation constant of 8.2 μM. Mtd tended to increase the rate of I(K(erg)) deactivation in a voltage-dependent fashion. EDDP (10 μM) had no effect on I(K(erg)), while EMDP (10μM) slightly suppressed it. In GH₃ cells incubated with naloxone (30 μM), the Mtd-induced inhibition of I(K(erg)) remained unaltered. Under cell-attached voltage-clamp recordings, Mtd increased the frequency of spontaneous action currents with no change in current amplitude. Similarly, Mtd can suppress I(K(erg)) in differentiated NG108-15 cells; dynorphin A(1-13) did not reverse Mtd-induced inhibition of I(K(erg)). This study shows that Mtd has a depressant effect on I(K(erg)), and suggests its ability to affect membrane excitability and prolactin secretion. The cyclization of Mtd, in which EDDP and EMDP are formed, tends to be critical in removal of the Mtd binding to erg K+ channel.
PDF file, 114K, CTMP mRNA expression data adapted from GEO public available microarray database, ... more PDF file, 114K, CTMP mRNA expression data adapted from GEO public available microarray database, GSE3744.
[[abstract]]Purpose: The goal of targeted therapy is to identify the suitable target molecules to... more [[abstract]]Purpose: The goal of targeted therapy is to identify the suitable target molecules to be inhibited, in order to achieve the best antitumor effect. The classical viewpoint is that inhibitor acting on single target allows selectivity and less adverse effect. However, clinical experience revealed that almost relapsed cancer patients developed drug resistance, often due to the activation or development of alternative signaling pathways or mutations that single target drugs are unable to effectively inhibit them. A current trend in the development of kinase inhibitors is the assumption that multi targeted therapy, which targets at several signaling pathways simultaneously, is more effective than single targeted therapy. Thus, paradigm in designing new anticancer drug is shifted: The drugs that act on multiple targets might have a better chance of inhibiting cancer cell proliferation than drugs that act on a single target. The objective of this research is aimed at identifying a multi-targeted kinase inhibitor as a development candidate for cancer therapy. Material and Method: We established Structure–Activity Relationship (S.A.R.) study based on 800 compounds that were synthesized by High Throughput Parallel Synthesis. Scaffold hopping approach by changing pharmacophore moiety had led us to discover DBPR114 as a multiple-targeted kinase inhibitor. Results: We discovered a novel multiple-targeted kinase inhibitor, DBPR114, that effectively inhibited 15 kinases in a panel of 57 oncogenic related kinases profiling, particularly against to Aurora kinase A and B, FLT-1, FLT-3 and c-Met in nanomolar range. In pharmacological study, DBPR114 significantly shrank tumor in 8 different xenograft models including Mia-Paca2, AsPC-1 (pancreatic carcinoma), Hep3B (hepatocellular carcinoma), MKN-45 (gastric carcinoma), MOLM-13 and MV4;11 (acute myeloid leukemia), NTUB-1 (bladder cancer), and Colo-205 (colorectal carcinoma) at a dose of 3 to 20 mg/kg by intravenous administration without significant adverse effect in most group of in vivo evaluations. Conclusion: This multiple targeting inhibitory properties plays a major role to shrinks tumor growth of various cancer cells in vivo and in vivo such as MOLM-13, MV4;11, MKN45, Colo-205, Mia-Paca2 and NTUB-1. The broad spectrum of anti-tumor activity of BPR1K0871 provides a great potential to become a promising multi-targeted kinase inhibitors as next generation of anti-cancer drug
Colon cancer has high incidence rate in the world and the early stage of colon cancer can be cure... more Colon cancer has high incidence rate in the world and the early stage of colon cancer can be cured by surgical therapy. However, it remains difficult to predict the prognostic outcome of colon cancer patients. STK4 is considered as a potential tumor suppressor, which plays an important role in Hippo pathway to control the organ size and the inhibition ability of cell-cell contact. The major aim of this study is focused on the investigation of prognostic value of STK4 in colon cancer. By immunohistochemistry assay, we examined the expression of STK4 in 140 pairs normal and tumor colon cancer specimens. The relationship between STK4 expression and clinicopathological factors as well as patient survival were analyzed and the results showed that STK4 was significantly downregulated in tumor tissues compared to their corresponding non-tumor part (P<0.01) and that was significantly associated with tumor size (P=0.003), distal metastasis (P=0.03), disease recurrence and poor survival (P<0.005). Moreover, loss of STK4 expression showed a significant poor outcome in colon cancer patients by univariate and multivariate analysis. These results indicated that there is a positive correlation in STK4 expression and prognosis and survival of colon cancer patients. Loss of STK4 expression displayed poor outcome. The conclusion is that STK4 can be used as a prognostic maker to predict patient survival and play a role in metastasis suppression of colorectal cancer. Citation Format: Yu-Cheng Lee, Chia-Ning Yang, Tai-I Hsu, Pei-Jung Lu. STK4 downregulation promotes tumor invasion/migration and is associated with poor prognosis in human colon cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1146. doi:10.1158/1538-7445.AM2013-1146
Methadone (Mtd) is a widely used opioid drug associated with the side effect of hyperprolactinemi... more Methadone (Mtd) is a widely used opioid drug associated with the side effect of hyperprolactinemia. The mechanism of how Mtd induces prolactin secretion remains unclear. The effects of Mtd and its two main metabolites (EDDP: (±)-2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium percholarate and EMDP: 2-ethyl-5-methyl-3,3-dipnehyl-1-pyrroline) on ion currents were investigated in GH₃ pituitary tumor cells. Hyperpolarization-elicited K+ currents in GH₃ cells bathed in a high-K(+), Ca(2+)-free solution were studied to evaluate the effects of Mtd and other related compounds on the ether-à-go-go-related-gene (erg) K(+) current (I(K(erg))). Mtd suppressed the amplitude of I(K(erg)) in a concentration-dependent manner with an IC(50) value of 10.4 μM. With the aid of a minimal binding scheme, the inhibitory action of Mtd on I(K(erg)) was estimated with a dissociation constant of 8.2 μM. Mtd tended to increase the rate of I(K(erg)) deactivation in a voltage-dependent fashion. EDDP (10 μM) had no effect on I(K(erg)), while EMDP (10μM) slightly suppressed it. In GH₃ cells incubated with naloxone (30 μM), the Mtd-induced inhibition of I(K(erg)) remained unaltered. Under cell-attached voltage-clamp recordings, Mtd increased the frequency of spontaneous action currents with no change in current amplitude. Similarly, Mtd can suppress I(K(erg)) in differentiated NG108-15 cells; dynorphin A(1-13) did not reverse Mtd-induced inhibition of I(K(erg)). This study shows that Mtd has a depressant effect on I(K(erg)), and suggests its ability to affect membrane excitability and prolactin secretion. The cyclization of Mtd, in which EDDP and EMDP are formed, tends to be critical in removal of the Mtd binding to erg K+ channel.
PDF file, 114K, CTMP mRNA expression data adapted from GEO public available microarray database, ... more PDF file, 114K, CTMP mRNA expression data adapted from GEO public available microarray database, GSE3744.
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