Source:http://linkedlifedata.com/resource/pubmed/id/17363487
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| Predicate | Object |
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| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
3
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| pubmed:dateCreated |
2007-3-16
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| pubmed:abstractText |
P276-00, a flavone that inhibits cyclin-dependent kinases, has been identified by us recently as a novel antineoplastic agent. In this study, we have selected a panel of human tumor cell lines and xenografts to allow determination of selectivity and efficacy of P276-00. When tested against a panel of 16 cisplatin-sensitive and cisplatin-resistant cell lines, the antiproliferative potential of P276-00 was found to be approximately 30-fold higher than cisplatin. Studies to show tumor sensitivity using clonogenic assay in 22 human xenografts indicated that P276-00 was approximately 26-fold more potent than cisplatin, and further, it was also found to be active against cisplatin-resistant tumors of central nervous system, melanoma, prostate, and renal cancers. Further, we studied the effects of P276-00 on cell cycle progression by flow cytometry using asynchronous and synchronous population of tumor and normal cells. Asynchronous population of human prostate carcinoma (PC-3) and human promyelocytic leukemia (HL-60) cells when exposed to P276-00 showed arrest of slow-growing PC-3 cells in G(2)-M with no significant apoptosis observed up to 72 h. Unlike PC-3, significant apoptosis was seen in fast-growing HL-60 cells at 6 h. However, synchronized human non-small cell lung carcinoma (H-460) and human normal lung fibroblast (WI-38) cells showed arrest of cells in G(1). H-460 cells undergo apoptosis, which increases with longer exposure to the compound and also after exposure to P276-00 for 48 h followed by recovery. In contrast, the normal cells (WI-38) remain arrested in G(1) with no significant apoptosis up to 72 h of exposure and also after 48 h of P276-00 treatment followed by recovery, confirming our previous results that P276-00 was less effective against normal cells compared with cancer cells. After promising in vitro results, P276-00 was checked for in vivo efficacy in murine tumor and human xenograft models. Growth inhibition of murine colon cancer (CA-51) was significant when P276-00 was administered i.p. at 50 mg/kg daily for 20 treatments. However, in murine lung carcinoma model (Lewis lung), an increased dose of 60 mg/kg (30 mg/kg twice daily) administered every alternate day i.p. for seven treatments showed significant inhibition in the growth. Further studies were undertaken to establish the efficacy profile of P276-00 in human tumor xenograft models. In the two xenograft models studied, P276-00 showed potent in vivo antitumor potential. Compound P276-00 at a dose of 35 mg/kg administered daily via the i.p. route for 10 days showed significant (P < 0.05) inhibition in the growth of human colon carcinoma HCT-116 xenograft. Furthermore, P276-00 at a dose of 50 mg/kg once daily and 30 mg/kg twice daily administered via i.p. route for 20 treatments significantly (P < 0.05) inhibited growth of human non-small cell lung carcinoma H-460 xenograft. Thus, the in vitro cellular potency, together with in vivo antitumor activity, confirms the potential of P276-00, a cyclin-dependent kinase inhibitor as an anticancer molecule.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Cisplatin,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Flavones,
http://linkedlifedata.com/resource/pubmed/chemical/P276-00
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| pubmed:status |
MEDLINE
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| pubmed:month |
Mar
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| pubmed:issn |
1535-7163
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| pubmed:author |
pubmed-author:BhatiaDimpleD,
pubmed-author:ChileShailajaS,
pubmed-author:FiebigHeinz-HerbertHH,
pubmed-author:JoshiKalpana SKS,
pubmed-author:MahajanPravinP,
pubmed-author:MaierArminA,
pubmed-author:RathosMaggie JMJ,
pubmed-author:SharmaSomeshS,
pubmed-author:ShenoySatyendraS,
pubmed-author:SivakumarMeenakshiM,
pubmed-author:SnopeF CFC
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| pubmed:issnType |
Print
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| pubmed:volume |
6
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
926-34
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| pubmed:dateRevised |
2009-11-19
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| pubmed:meshHeading |
pubmed-meshheading:17363487-Animals,
pubmed-meshheading:17363487-Antineoplastic Agents,
pubmed-meshheading:17363487-Apoptosis,
pubmed-meshheading:17363487-Cell Proliferation,
pubmed-meshheading:17363487-Cisplatin,
pubmed-meshheading:17363487-Cyclin-Dependent Kinases,
pubmed-meshheading:17363487-Disease Models, Animal,
pubmed-meshheading:17363487-Drug Resistance, Neoplasm,
pubmed-meshheading:17363487-Flavones,
pubmed-meshheading:17363487-Flow Cytometry,
pubmed-meshheading:17363487-G2 Phase,
pubmed-meshheading:17363487-Humans,
pubmed-meshheading:17363487-Mice,
pubmed-meshheading:17363487-Mice, Inbred BALB C,
pubmed-meshheading:17363487-Mice, SCID,
pubmed-meshheading:17363487-Neoplasms, Experimental,
pubmed-meshheading:17363487-Tumor Cells, Cultured,
pubmed-meshheading:17363487-Xenograft Model Antitumor Assays
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| pubmed:year |
2007
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| pubmed:articleTitle |
P276-00, a novel cyclin-dependent inhibitor induces G1-G2 arrest, shows antitumor activity on cisplatin-resistant cells and significant in vivo efficacy in tumor models.
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| pubmed:affiliation |
Department of Pharmacology, Nicholas Piramal Research Center, Nicholas Piramal India Ltd., 1-Nirlon Complex, Goregaon (East), Mumbai 400 063, India. kjoshi@nicholaspiramal.co.in
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| pubmed:publicationType |
Journal Article
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