title: Roscovitine synergizes with conventional chemo-therapeutic drugs to induce efficient apoptosis of human colorectal cancer cells.
abstract: OBJECTIVE
  To examine the ability of cyclin-dependent kinase inhibitor (CDKI) roscovitine (Rosco) to enhance the antitumor effects of conventional chemotherapeutic agents acting by different mechanisms against human colorectal cancer.
  
  
  METHODS
  Human colorectal cancer cells were treated, individually and in combination, with Rosco, taxol, 5-Fluorouracil (5-FU), doxorubicine or vinblastine. The antiproliferative effects and the type of interaction of Rosco with tested chemotherapeutic drugs were determined. Cell cycle alterations were investigated by fluorescence-activated cell sorter FACS analysis. Apoptosis was determined by DNA fragmentation assay.
  
  
  RESULTS
  Rosco inhibited the proliferation of tumor cells in a time- and dose-dependent manner. The efficacies of all tested chemotherapeutic drugs were markedly enhanced 3.0-8.42 multiply 10(3) and 130-5.28 multiply 10(3) fold in combination with 5 and 10 microg/mL Rosco, respectively. The combination of Rosco and chemotherapeutic drugs inhibited the growth of human colorectal cancer cells in an additive or synergistic fashion, and in a time and dose dependent manner. Rosco induced apoptosis and synergized with tested chemotherapeutic drugs to induce efficient apoptosis in human colorectal cancer cells. Sequential, inverted sequential and simultaneous treatment of cancer cells with combinations of chemotherapeutic drugs and Rosco arrested the growth of human colorectal cancer cells at various phases of the cell cycle as follows: Taxol/Rosco (G2/M- and S-phases), 5-FU/Rosco (S-phase), Dox/Rosco (S-phase) and Vinb/Rosco (G2/M- and S-phases).
  
  
  CONCLUSIONS
  Since the efficacy of many anticancer drugs depends on their ability to induce apoptotic cell death, modulation of this parameter by cell cycle inhibitors may provide a novel chemo-preventive and chemotherapeutic strategy for human colorectal cancer.
authors.affiliation: Molecular Biology Program, Department of Biological Sciences, Faculty of Science, Kuwait University, PO Box 5696, Safaat 13006, Kuwait. abaza@kuc01.kuniv.edu.kw
authors.forename: Mohamed Salah I
authors.initials: MS
authors.lastname: Abaza
authors.forename: Abdul-Majeed A
authors.initials: AM
authors.lastname: Bahman
authors.forename: Rajaa J
authors.initials: RJ
authors.lastname: Al-Attiyah
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use*; D000077546:Roscovitine; D013997:Time Factors; D014747:Vinblastine / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D011687:Purines; D000077546:Roscovitine; D014747:Vinblastine; D004317:Doxorubicin; D017239:Paclitaxel; D005472:Fluorouracil
references.citation: Cancer Biol Ther. 2002 Jul-Aug;1(4):420-5
references.pmid: 12432259
references.citation: Expert Opin Investig Drugs. 2006 Jan;15(1):23-38
references.pmid: 16370931
references.citation: Cancer Res. 1999 Apr 15;59(8):1903-10
references.pmid: 10213499
references.citation: Eur J Cancer. 1997 Apr;33(4):566-74
references.pmid: 9274436
references.citation: Cancer Res. 2003 May 15;63(10):2513-7
references.pmid: 12750274
references.citation: EMBO J. 2004 Dec 8;23(24):4868-75
references.pmid: 15549137
references.citation: Oncogene. 2000 Jun 22;19(27):3059-68
references.pmid: 10871858
references.citation: Carcinogenesis. 2002 May;23(5):687-96
references.pmid: 12016139
references.citation: Int J Oncol. 2002 Jul;21(1):95-101
references.pmid: 12063555
references.citation: Curr Med Chem. 1999 Sep;6(9):859-75
references.pmid: 10495356
references.citation: Oncogene. 2001 Sep 20;20(42):5951-63
references.pmid: 11593402
references.citation: J Biol Chem. 1997 Oct 10;272(41):26056-61
references.pmid: 9325343
references.citation: Tumour Biol. 2003 Sep-Oct;24(5):241-57
references.pmid: 15001837
references.citation: Neuroreport. 1999 Aug 20;10(12):2563-7
references.pmid: 10574370
references.citation: Int J Cancer. 2001 Aug 15;93(4):481-8
references.pmid: 11477551
references.citation: J Cell Biol. 1994 Feb;124(4):619-26
references.pmid: 8106557
references.citation: CA Cancer J Clin. 2000 Jan-Feb;50(1):7-33
references.pmid: 10735013
references.citation: Clin Cancer Res. 2005 Nov 15;11(22):8158-71
references.pmid: 16299248
references.citation: Eur J Biochem. 1997 Jan 15;243(1-2):527-36
references.pmid: 9030781
references.citation: Clin Exp Metastasis. 1998 Jan;16(1):50-61
references.pmid: 9502077
references.citation: Mol Cell Biol. 2001 Apr;21(8):2755-66
references.pmid: 11283255
references.citation: Oncogene. 1999 Dec 9;18(52):7409-22
references.pmid: 10602500
references.citation: Science. 1998 Jan 23;279(5350):509-14
references.pmid: 9438836
references.citation: J Biol Chem. 1997 Feb 21;272(8):5214-8
references.pmid: 9030591
references.citation: Semin Oncol. 2001 Aug;28(4 Suppl 15):62-6
references.pmid: 11685731
references.citation: Br J Biomed Sci. 2001;58(4):226-9
references.pmid: 11787998
references.citation: Anticancer Res. 1998 Jan-Feb;18(1A):301-7
references.pmid: 9568094
references.citation: J Biol Chem. 1993 Jul 25;268(21):15868-77
references.pmid: 8340412
references.citation: Adv Cancer Res. 1996;68:67-108
references.pmid: 8712071
references.citation: Int J Cancer. 2003 Sep 10;106(4):486-95
references.pmid: 12845642
references.citation: Prog Cell Cycle Res. 1995;1:351-63
references.pmid: 9552377
references.citation: Exp Cell Res. 1998 Jul 10;242(1):92-9
references.pmid: 9665806
references.citation: Urol Oncol. 2001 May;6(3):111-115
references.pmid: 11344001
references.citation: Nature. 2004 Oct 21;431(7011):1011-7
references.pmid: 15496928
references.citation: Cancer Lett. 2002 Jun 6;180(1):7-12
references.pmid: 11911964
references.citation: Eur J Biochem. 1997 Jan 15;243(1-2):518-26
references.pmid: 9030780
references.citation: Chembiochem. 2002 Jul 2;3(7):596-603
references.pmid: 12324993
references.citation: Nat Med. 1997 Feb;3(2):231-4
references.pmid: 9018245