7-Chloro-6-piperidin-1-yl-quinoline-5,8-dione (PT-262), a novel synthetic compound induces lung carcinoma cell death associated with inhibiting ERK and CDC2 phosphorylation via a p53-independent pathway.

Abstract

BACKGROUND:

The derivatives of 5,8-quinolinedione have been shown to exert anticancer activities. A new synthetic compound 7-chloro-6-piperidin-1-yl-quinoline-5,8-dione (designed as PT-262) derived from 6,7-dichloroquinoline-5,8-dione on its anticancer activity was investigated in this study.

MATERIALS AND METHODS:

PT-262 was synthesized as the following: triethylamine (0.56 ml, 5.1 mmol) was added dropwise to a solution of 6,7-dichloroquinoline-5,8-dione (1.00 g, 4.4 mmol) and piperidine (0.50 ml, 5.1 mmol) in 150 ml of benzene with stirring at room temperature for 5 min, and the solvent was removed using rotary evaporator to give a dark brown solid. PT-262 was purified by flash chromatography using 50% ethyl acetate/hexanes to elute that displayed as brown solids. To examine the induction of apoptosis following PT-262 treatment, the lung cancer cells were subjected to apoptotic cell observation, caspase activation, and mitochondrial functional assays. The protein levels of phosphorylated ERK and CDC2 after treatment with PT-262 were analyzed by Western blot.

RESULTS:

Treatment with 1-20 microM PT-262 for 24 h induced cytotoxicity via a concentration-dependent manner in human lung cancer cells. PT-262 induced the loss of mitochondrial membrane potential and elevated the caspase-3 activation and apoptosis. Interestingly, the phosphorylation of ERK was inhibited by PT-262. The IC50 value of ERK phosphorylation inhibition was approximate around 5 microM. Treatment with a specific MEK1/2 (the upstream of ERK) inhibitor, PD98059, increased the PT-262-induced cytotoxicity in lung cancer cells. Moreover, PT-262 did not alter the protein expression of tumor suppressor p53. PT-262 elicited the cytotoxicity and accumulated the G2/M fractions in both the p53-wild type and p53-null lung cancer cells. The mitosis-regulated protein levels of cyclin B1 and phospho-CDC2 at Thr14, Tyr15, and Thr161 were repressed by PT-262 in these cells.

CONCLUSION:

PT-262 suppresses the phosphorylation of ERK and CDC2 associated with proliferation inhibition via a p53-independent pathway in human lung cancer cells.

• Authors: Tzu-Sheng Hsu, Chinpiao Chen, Pei-Ting Lee, Shu-Jun Chiu, Huei-Fang Liu, Chih-Chien Tsai, Jui-I Chao
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 62 Issue 5 Pg. 799-808 (Oct 2008) ISSN: 0344-5704 [Print] Germany
• PMID: 18193228 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 7-chloro-6-piperidin-1-ylquinoline-5,8-dione
• Antineoplastic Agents
• Quinolones
• Quinones
• Tumor Suppressor Protein p53
• CDC2 Protein Kinase
• Extracellular Signal-Regulated MAP Kinases
• Mitogen-Activated Protein Kinases

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• CDC2 Protein Kinase (antagonists & inhibitors)
• Carcinoma (drug therapy, pathology)
• Cell Count
• Cell Cycle (drug effects)
• Cell Death (drug effects)
• Cell Division (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors)
• Humans
• Lung Neoplasms (drug therapy, pathology)
• Membrane Potentials (drug effects)
• Mitochondrial Membranes (drug effects)
• Mitogen-Activated Protein Kinases (antagonists & inhibitors)
• Phosphorylation
• Quinolones (chemistry, pharmacology)
• Quinones (chemistry, pharmacology)
• Signal Transduction (drug effects)
• Tumor Suppressor Protein p53 (physiology)