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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

BL-AD008 induces apoptosis in HeLa cells(A) Cell viability was measured by the MTT assay in A1-treated and BL-AD008-treated HeLa cells. (B) The cellular morphology was observed without or with BL-AD008 under the inverted microscopy and fluorescent microscopy, respectively. (C) Apoptosis was determined by the analyses of Annexin staining.
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Figure 5: BL-AD008 induces apoptosis in HeLa cells(A) Cell viability was measured by the MTT assay in A1-treated and BL-AD008-treated HeLa cells. (B) The cellular morphology was observed without or with BL-AD008 under the inverted microscopy and fluorescent microscopy, respectively. (C) Apoptosis was determined by the analyses of Annexin staining.

Mentions: We found that BL-AD008 caused a remarkable anti-proliferative effect on HeLa and C4-I cell growth in dose-dependent manner, and the treatment with 600 nM BL-AD008 for 24h resulted in almost 50% inhibition in the HeLa cells (Figure 5A). To characterize the BL-AD008-induced HeLa cell apoptosis, we observed the morphologic changes in the cells. When the cells were cultured with 600nM BL-AD008 for 24 h, the apoptotic alterations were also observed under the inverted microscopy. And, the marked apoptotic morphologic alterations were observed by Hoechst 33258 staining under fluorescence microscopy (Figure 5B). In addition, apoptosis was further evaluated by Annexin-V/PI double staining. BL-AD008 markedly induced the increase of apoptotic ratio in HeLa cells (Figure 5C).


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)

BL-AD008 induces apoptosis in HeLa cells(A) Cell viability was measured by the MTT assay in A1-treated and BL-AD008-treated HeLa cells. (B) The cellular morphology was observed without or with BL-AD008 under the inverted microscopy and fluorescent microscopy, respectively. (C) Apoptosis was determined by the analyses of Annexin staining.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: BL-AD008 induces apoptosis in HeLa cells(A) Cell viability was measured by the MTT assay in A1-treated and BL-AD008-treated HeLa cells. (B) The cellular morphology was observed without or with BL-AD008 under the inverted microscopy and fluorescent microscopy, respectively. (C) Apoptosis was determined by the analyses of Annexin staining.
Mentions: We found that BL-AD008 caused a remarkable anti-proliferative effect on HeLa and C4-I cell growth in dose-dependent manner, and the treatment with 600 nM BL-AD008 for 24h resulted in almost 50% inhibition in the HeLa cells (Figure 5A). To characterize the BL-AD008-induced HeLa cell apoptosis, we observed the morphologic changes in the cells. When the cells were cultured with 600nM BL-AD008 for 24 h, the apoptotic alterations were also observed under the inverted microscopy. And, the marked apoptotic morphologic alterations were observed by Hoechst 33258 staining under fluorescence microscopy (Figure 5B). In addition, apoptosis was further evaluated by Annexin-V/PI double staining. BL-AD008 markedly induced the increase of apoptotic ratio in HeLa cells (Figure 5C).

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