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Systems biology network-based discovery of a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer.

Fu L, Zhang S, Zhang L, Tong X, Zhang J, Zhang Y, Ouyang L, Liu B, Huang J - Oncotarget (2015)

Bottom Line: Subsequently, we screened a series of candidate compounds targeting AMPK/ZIPK, synthesized some compounds and eventually discovered a novel dual-target activator (BL-AD008).Additionally, we found that BL-AD008-induced apoptosis was affected by the combination of AMPK and ZIPK.Then, we found that BL-AD008 bear its anti-tumor activities and induced apoptosis by targeting AMPK/ZIPK in vivo.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.

ABSTRACT
The aim of this study was to discover a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer. In this study, we systematically constructed the global protein-protein interaction (PPI) network and predicted apoptosis-related protein connections by the Naïve Bayesian model. Then, we identified some classical apoptotic PPIs and other previously unrecognized PPIs between apoptotic kinases, such as AMPK and ZIPK. Subsequently, we screened a series of candidate compounds targeting AMPK/ZIPK, synthesized some compounds and eventually discovered a novel dual-target activator (BL-AD008). Moreover, we found BL-AD008 bear remarkable anti-proliferative activities toward cervical cancer cells and could induce apoptosis by death-receptor and mitochondrial pathways. Additionally, we found that BL-AD008-induced apoptosis was affected by the combination of AMPK and ZIPK. Then, we found that BL-AD008 bear its anti-tumor activities and induced apoptosis by targeting AMPK/ZIPK in vivo. In conclusion, these results demonstrate the ability of systems biology network to identify some key apoptotic kinase targets AMPK and ZIPK; thus providing a dual-target small molecule activator (BL-AD008) as a potential new apoptosis-modulating drug in future cervical cancer therapy.

No MeSH data available.


Related in: MedlinePlus

A schematic model of network prediction and experimental validation of a novel AMPK/ZIPK activator BL-AD008 in cervical cancer(A) We systematically constructed the global protein-protein interaction (PPI) network and integrated four different biological evidence to predict apoptosis-related protein connections by the Naïve Bayesian model; (B) Utilizing the Naïve Bayesian model and four golden standards, we identified some key apoptotic kinase targets, such as AMPK and ZIPK in cancer; (C) We screened many candidate compounds, synthesized some compounds and eventually designed a novel dual-target activator (BL-AD008) that induced the death-receptor and mitochondrial apoptosis, which was affected by AMPK and ZIPK in cervical cancer in vitro and in vivo.
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Figure 10: A schematic model of network prediction and experimental validation of a novel AMPK/ZIPK activator BL-AD008 in cervical cancer(A) We systematically constructed the global protein-protein interaction (PPI) network and integrated four different biological evidence to predict apoptosis-related protein connections by the Naïve Bayesian model; (B) Utilizing the Naïve Bayesian model and four golden standards, we identified some key apoptotic kinase targets, such as AMPK and ZIPK in cancer; (C) We screened many candidate compounds, synthesized some compounds and eventually designed a novel dual-target activator (BL-AD008) that induced the death-receptor and mitochondrial apoptosis, which was affected by AMPK and ZIPK in cervical cancer in vitro and in vivo.

Mentions: In conclusion, we demonstrate the ability of our Naïve Bayesian model-based network for identifying the key double targets AMPK and ZIPK, and provide the dual-target activator (BL-AD008) as a potential new apoptosis-modulating drug for cervical cancer therapy (Figure 10). Therefore, these findings would lead to a comprehensive mechanistic insights into identification of more ideal dual targets as well as discovery of more new kinase activators. Moreover, it would also provide a basis for developing more new systems biology network-based approaches and more promising strategies for future cancer therapeutics.


Systems biology network-based discovery of a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer.

Fu L, Zhang S, Zhang L, Tong X, Zhang J, Zhang Y, Ouyang L, Liu B, Huang J - Oncotarget (2015)

A schematic model of network prediction and experimental validation of a novel AMPK/ZIPK activator BL-AD008 in cervical cancer(A) We systematically constructed the global protein-protein interaction (PPI) network and integrated four different biological evidence to predict apoptosis-related protein connections by the Naïve Bayesian model; (B) Utilizing the Naïve Bayesian model and four golden standards, we identified some key apoptotic kinase targets, such as AMPK and ZIPK in cancer; (C) We screened many candidate compounds, synthesized some compounds and eventually designed a novel dual-target activator (BL-AD008) that induced the death-receptor and mitochondrial apoptosis, which was affected by AMPK and ZIPK in cervical cancer in vitro and in vivo.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480736&req=5

Figure 10: A schematic model of network prediction and experimental validation of a novel AMPK/ZIPK activator BL-AD008 in cervical cancer(A) We systematically constructed the global protein-protein interaction (PPI) network and integrated four different biological evidence to predict apoptosis-related protein connections by the Naïve Bayesian model; (B) Utilizing the Naïve Bayesian model and four golden standards, we identified some key apoptotic kinase targets, such as AMPK and ZIPK in cancer; (C) We screened many candidate compounds, synthesized some compounds and eventually designed a novel dual-target activator (BL-AD008) that induced the death-receptor and mitochondrial apoptosis, which was affected by AMPK and ZIPK in cervical cancer in vitro and in vivo.
Mentions: In conclusion, we demonstrate the ability of our Naïve Bayesian model-based network for identifying the key double targets AMPK and ZIPK, and provide the dual-target activator (BL-AD008) as a potential new apoptosis-modulating drug for cervical cancer therapy (Figure 10). Therefore, these findings would lead to a comprehensive mechanistic insights into identification of more ideal dual targets as well as discovery of more new kinase activators. Moreover, it would also provide a basis for developing more new systems biology network-based approaches and more promising strategies for future cancer therapeutics.

Bottom Line: Subsequently, we screened a series of candidate compounds targeting AMPK/ZIPK, synthesized some compounds and eventually discovered a novel dual-target activator (BL-AD008).Additionally, we found that BL-AD008-induced apoptosis was affected by the combination of AMPK and ZIPK.Then, we found that BL-AD008 bear its anti-tumor activities and induced apoptosis by targeting AMPK/ZIPK in vivo.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.

ABSTRACT
The aim of this study was to discover a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer. In this study, we systematically constructed the global protein-protein interaction (PPI) network and predicted apoptosis-related protein connections by the Naïve Bayesian model. Then, we identified some classical apoptotic PPIs and other previously unrecognized PPIs between apoptotic kinases, such as AMPK and ZIPK. Subsequently, we screened a series of candidate compounds targeting AMPK/ZIPK, synthesized some compounds and eventually discovered a novel dual-target activator (BL-AD008). Moreover, we found BL-AD008 bear remarkable anti-proliferative activities toward cervical cancer cells and could induce apoptosis by death-receptor and mitochondrial pathways. Additionally, we found that BL-AD008-induced apoptosis was affected by the combination of AMPK and ZIPK. Then, we found that BL-AD008 bear its anti-tumor activities and induced apoptosis by targeting AMPK/ZIPK in vivo. In conclusion, these results demonstrate the ability of systems biology network to identify some key apoptotic kinase targets AMPK and ZIPK; thus providing a dual-target small molecule activator (BL-AD008) as a potential new apoptosis-modulating drug in future cervical cancer therapy.

No MeSH data available.


Related in: MedlinePlus