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In Silico Identification and In Vitro and In Vivo Validation of Anti-Psychotic Drug Fluspirilene as a Potential CDK2 Inhibitor and a Candidate Anti-Cancer Drug.

Shi XN, Li H, Yao H, Liu X, Li L, Leung KS, Kung HF, Lu D, Wong MH, Lin MC - PLoS ONE (2015)

Bottom Line: Our results showed that oral fluspirilene treatment significantly inhibited tumor growth.Moreover, the cocktail treatment with fluspirilene and 5-fluorouracil exhibited the highest therapeutic effect.In view of the fact that fluspirilene has a long history of safe human use, our discovery of fluspirilene as a potential anti-HCC drug may present an immediately applicable clinical therapy.

View Article: PubMed Central - PubMed

Affiliation: Biotechnology Center, Kunming Medical University, Kunming, Yunnan, China; Department of Medicine, Southwest Guizhou Vocational and Technical College for Nationalities, Guizhou, China.

ABSTRACT
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Surgical resection and conventional chemotherapy and radiotherapy ultimately fail due to tumor recurrence and HCC's resistance. The development of novel therapies against HCC is thus urgently required. The cyclin-dependent kinase (CDK) pathways are important and well-established targets for cancer treatment. In particular, CDK2 is a key factor regulating the cell cycle G1 to S transition and a hallmark for cancers. In this study, we utilized our free and open-source protein-ligand docking software, idock, prospectively to identify potential CDK2 inhibitors from 4,311 FDA-approved small molecule drugs using a repurposing strategy and an ensemble docking methodology. Sorted by average idock score, nine compounds were purchased and tested in vitro. Among them, the anti-psychotic drug fluspirilene exhibited the highest anti-proliferative effect in human hepatocellular carcinoma HepG2 and Huh7 cells. We demonstrated for the first time that fluspirilene treatment significantly increased the percentage of cells in G1 phase, and decreased the expressions of CDK2, cyclin E and Rb, as well as the phosphorylations of CDK2 on Thr160 and Rb on Ser795. We also examined the anti-cancer effect of fluspirilene in vivo in BALB/C nude mice subcutaneously xenografted with human hepatocellular carcinoma Huh7 cells. Our results showed that oral fluspirilene treatment significantly inhibited tumor growth. Fluspirilene (15 mg/kg) exhibited strong anti-tumor activity, comparable to that of the leading cancer drug 5-fluorouracil (10 mg/kg). Moreover, the cocktail treatment with fluspirilene and 5-fluorouracil exhibited the highest therapeutic effect. These results suggested for the first time that fluspirilene is a potential CDK2 inhibitor and a candidate anti-cancer drug for the treatment of human hepatocellular carcinoma. In view of the fact that fluspirilene has a long history of safe human use, our discovery of fluspirilene as a potential anti-HCC drug may present an immediately applicable clinical therapy.

No MeSH data available.


Related in: MedlinePlus

Redocking accuracy of idock for the 44 CDK2 complexes.The RMSD distributions of pose 1 and pose m are shown in black and red, respectively. 10 and 28 points are below the baseline of RMSD = 2Å for pose 1 and pose m, respectively.
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pone.0132072.g001: Redocking accuracy of idock for the 44 CDK2 complexes.The RMSD distributions of pose 1 and pose m are shown in black and red, respectively. 10 and 28 points are below the baseline of RMSD = 2Å for pose 1 and pose m, respectively.

Mentions: Fig 1 plots the distribution of RMSD values of the first pose (denoted as pose 1), which was predicted to have the lowest free energy among the nine poses, as well as the distribution of RMSD values of the pose that has the minimum RMSD among the nine poses (denoted as pose m). Detailed explanation and the rationale of selection of these two kinds of poses can be found in [6]. Semantically, the RMSD value of pose 1 (denoted as RMSD1) and the RMSD value of pose m (denoted as RMSDm) reflect the redocking accuracy if only the top one and top nine predicted poses are considered, respectively. By definition, RMSDm ≤ RMSD1 is always guaranteed. Out of the 44 redocking trials, 10 trials produced RMSD1 < 2Å and 28 trials produced RMSDm < 2Å. These redocking results reflect to some extent the appropriateness of using idock to dock compounds against CDK2 structures.


In Silico Identification and In Vitro and In Vivo Validation of Anti-Psychotic Drug Fluspirilene as a Potential CDK2 Inhibitor and a Candidate Anti-Cancer Drug.

Shi XN, Li H, Yao H, Liu X, Li L, Leung KS, Kung HF, Lu D, Wong MH, Lin MC - PLoS ONE (2015)

Redocking accuracy of idock for the 44 CDK2 complexes.The RMSD distributions of pose 1 and pose m are shown in black and red, respectively. 10 and 28 points are below the baseline of RMSD = 2Å for pose 1 and pose m, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493148&req=5

pone.0132072.g001: Redocking accuracy of idock for the 44 CDK2 complexes.The RMSD distributions of pose 1 and pose m are shown in black and red, respectively. 10 and 28 points are below the baseline of RMSD = 2Å for pose 1 and pose m, respectively.
Mentions: Fig 1 plots the distribution of RMSD values of the first pose (denoted as pose 1), which was predicted to have the lowest free energy among the nine poses, as well as the distribution of RMSD values of the pose that has the minimum RMSD among the nine poses (denoted as pose m). Detailed explanation and the rationale of selection of these two kinds of poses can be found in [6]. Semantically, the RMSD value of pose 1 (denoted as RMSD1) and the RMSD value of pose m (denoted as RMSDm) reflect the redocking accuracy if only the top one and top nine predicted poses are considered, respectively. By definition, RMSDm ≤ RMSD1 is always guaranteed. Out of the 44 redocking trials, 10 trials produced RMSD1 < 2Å and 28 trials produced RMSDm < 2Å. These redocking results reflect to some extent the appropriateness of using idock to dock compounds against CDK2 structures.

Bottom Line: Our results showed that oral fluspirilene treatment significantly inhibited tumor growth.Moreover, the cocktail treatment with fluspirilene and 5-fluorouracil exhibited the highest therapeutic effect.In view of the fact that fluspirilene has a long history of safe human use, our discovery of fluspirilene as a potential anti-HCC drug may present an immediately applicable clinical therapy.

View Article: PubMed Central - PubMed

Affiliation: Biotechnology Center, Kunming Medical University, Kunming, Yunnan, China; Department of Medicine, Southwest Guizhou Vocational and Technical College for Nationalities, Guizhou, China.

ABSTRACT
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Surgical resection and conventional chemotherapy and radiotherapy ultimately fail due to tumor recurrence and HCC's resistance. The development of novel therapies against HCC is thus urgently required. The cyclin-dependent kinase (CDK) pathways are important and well-established targets for cancer treatment. In particular, CDK2 is a key factor regulating the cell cycle G1 to S transition and a hallmark for cancers. In this study, we utilized our free and open-source protein-ligand docking software, idock, prospectively to identify potential CDK2 inhibitors from 4,311 FDA-approved small molecule drugs using a repurposing strategy and an ensemble docking methodology. Sorted by average idock score, nine compounds were purchased and tested in vitro. Among them, the anti-psychotic drug fluspirilene exhibited the highest anti-proliferative effect in human hepatocellular carcinoma HepG2 and Huh7 cells. We demonstrated for the first time that fluspirilene treatment significantly increased the percentage of cells in G1 phase, and decreased the expressions of CDK2, cyclin E and Rb, as well as the phosphorylations of CDK2 on Thr160 and Rb on Ser795. We also examined the anti-cancer effect of fluspirilene in vivo in BALB/C nude mice subcutaneously xenografted with human hepatocellular carcinoma Huh7 cells. Our results showed that oral fluspirilene treatment significantly inhibited tumor growth. Fluspirilene (15 mg/kg) exhibited strong anti-tumor activity, comparable to that of the leading cancer drug 5-fluorouracil (10 mg/kg). Moreover, the cocktail treatment with fluspirilene and 5-fluorouracil exhibited the highest therapeutic effect. These results suggested for the first time that fluspirilene is a potential CDK2 inhibitor and a candidate anti-cancer drug for the treatment of human hepatocellular carcinoma. In view of the fact that fluspirilene has a long history of safe human use, our discovery of fluspirilene as a potential anti-HCC drug may present an immediately applicable clinical therapy.

No MeSH data available.


Related in: MedlinePlus