Abstract | PURPOSE: The potent anti- cancer capability of a novel CPT derivarate, 10-methoxy-9-nitrocamptothecin (MONCPT), has been demonstrated in our previous studies. The present study focuses on the in vitro and in vivo anti- cancer activities, the cell cycle arrest- and apoptosis-induction abilities of MONCPT on human bladder uroepithelial carcinoma 5637 cell line. MATERIALS AND METHODS: MTT assay and flow cytometric analyses were employed to evaluate the cell proliferation, cell cycle distribution and apoptosis of MONCPT-treated 5637 cells. Using 5637 xenografted nuce mice models, the in vivo anti- cancer capability of MONCPT were examined, as indicated by the decreased tumor volume and tumor weight. The effect of MONCPT on some of the key regulators of G2/M checkpoint and apoptosis, including CDKI-CDK- cyclin cascade, Kip1/p27 and Cip1/p21, PARP were examined using western blotting. RESULTS: The more potent anti- tumor activities of MONCPT than SN-38 against 5637 cells were indicated by the IC50 value (48 h) of 226.7 +/- 0.5 nM and 2031.0 +/- 0.5 nM, respectively. MONCPT treatment (0.1 microM) for 24 h caused the increment of G2/M population from 7.94% to 75.52%, indicating that MONCPT significantly triggered G2/M arrest. Moreover, MONCPT exposure (0.1 microM, 24 h) caused down-regulation of CDK7, p-Cdc2, and cyclinB1. Treatment with MONCPT (0.1 microM) for 48 h obviously induced apoptosis of 5637 cells, which was revealed by the accumulation of Annexin V-positive cells. The superior anti- tumor capabilities of MONCPT were further demonstrated in the human 5637 xenograft-bearing mice model. The administration of MONCPT at the dosages of 5, 10, 20 mg/kg for 15 days significantly inhibited the tumor growth with the inhibition rates of 64.8%, 86.2% and 96.5%, respectively. CONCLUSION: The present study displayed the significant in vitro anti-proliferative abilities of MONCPT on human ladder cancer 5637 cells, and in vivo tumor-inhibitory activities on xenograft models. In addition, MONCPT was demonstrated to induce G2/M arrest and apoptosis in 5637 cells. Our findings provide evidences for the anti- tumor activity of MONCPT in the ongoing preclinical assessment.
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Authors | Yue Zhu, Hai Jiang, Chong Zhang, Qiao-Jun He, Bo Yang, Lan-Juan Li, Hong Zhu |
Journal | Die Pharmazie
(Pharmazie)
Vol. 64
Issue 12
Pg. 823-8
(Dec 2009)
ISSN: 0031-7144 [Print] Germany |
PMID | 20095141
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 10-methoxy-9-nitrocamptothecin
- Antineoplastic Agents
- Cell Cycle Proteins
- Camptothecin
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Topics |
- Animals
- Antineoplastic Agents
(pharmacology)
- Apoptosis
(drug effects)
- Blotting, Western
- Camptothecin
(analogs & derivatives, pharmacology)
- Cell Cycle Proteins
(metabolism)
- Cell Division
(drug effects)
- Cell Line, Tumor
- G2 Phase
(drug effects)
- Humans
- Mice
- Mice, Nude
- Neoplasm Transplantation
- Up-Regulation
(drug effects)
- Urinary Bladder Neoplasms
(pathology)
- Xenograft Model Antitumor Assays
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