Sequential administration of camptothecin sensitizes human colon cancer HCT116 cells to paclitaxel via p21^(Cip1/WAF1)

다국어 초록 (Multilingual Abstract)

Colorectal cancer is the third leading cause of cancer-related death in Western countries. Chemotherapeutic agents with different mechanisms of action have shown an increase in cure rates. In the present study, we investigated the effect of a combination of low concentration of paclitaxel (taxol, 5 nM) and topoisomerase 1 inhibitor camptothecin (CPT) on HCT116 colon cancer cells. Although the viability of cells treated with taxol alone was similar to that of control cells, sequential treatment with taxol and CPT exhibited high cytotoxicity. However, the opposite sequence of treatment did not exert cytotoxic effects on HCT116 cells. This enhanced cytotoxicity of the sequential combination therapy was the result of mitotic arrest, which increased the level of p21^(Cip1/WAF1) through the p38 mitogen-activated protein kinase (MAPK) pathway. Knockdown by p21^(Cip1/WAF1) siRNA or treatment with a p38 inhibitor reduced the viability of cells sequentially exposed to taxol and CPT. Taken together, a low taxol concentration in combination with CPT induced mitotic arrest in HCT116 cells, leading to synergistic cell death through enhanced expression of p21^(Cip1/WAF1) and p38 MAPK pathway. Therefore, taxol could play a role as a sensitizer of CPT in colon cancer cells.

참고문헌 (Reference)

1 Deacon K, "p38 mitogen-activated protein kinase mediates cell death and p21-activated kinase mediates dell survival during chemotherapeutic drug-induced mitotic arrest" 14 : 2071-2087, 2003

2 Ciccarelli C, "p21WAF1 expression induced by MEK/ERK pathway activation or inhibition correlates with growth arrest, myogenic differentiationand onco-phenotype reversal in rhabdomyosarcoma cells" 4 : 41-, 2005

3 Furuta T, "p21CDKN1A allows the repair of replication-mediated DNA double-strand breaks induced by topoisomerase I and is inactivated by the checkpoint kinase inhibitor 7-hydro xystaurosporine" 25 : 2839-2849, 2006

4 Yang ZY, "p21 cyclin-dependent kinase inhibitor suppresses tumorigenicity in vivo" 1 : 1052-1056, 1995

5 Cui X, "cGMP-independent nitric oxide signaling and regulation of the cell cycle" 6 : 151-, 2005

6 Chen YG, "Tumor suppressing by p21WAF1 undergo normal development but are defective in G1 checkpoint control" 82 : 675-784, 1995

7 Zhou Y, "Transcriptional regulation of mitotic genes by camptothecin-induced DNA damage: microarray analysis of dose- and time-dependent effects" 62 : 1688-1695, 2002

8 Schmidt F, "Topotecan-based combination chemotherapy for human malignant glioma" 19 : 1217-1221, 1999

9 Pommier Y, "Topoisomerase I inhibitors: camptothecins and beyond" 6 : 789-802, 2006

10 Bacus SS, "Taxolinduced apoptosis depends on MAP kinase pathways (ERK and p38) and is independent of p53" 20 : 147-155, 2001

11 Tishler RB, "Taxol: a novel radiation sensitizer" 22 : 613-617, 1992

12 Manfredi JJ, "Taxol binds to cellular microtubules" 94 : 688-696, 1982

13 Wolpin BM, "Systemic treatment of colorectal cancer" 134 : 1296-1310, 2008

14 Bahadori HR, "Synergistic interaction between topotecan and microtubule-interfering agents" 48 : 188-196, 2001

15 Shamu CE, "Sister chromatid separation in frog egg extracts requires DNA topoisomerase II activity during anaphase" 117 : 921-934, 1992

16 Han Z, "Role of p21 in apoptosis and senescence of human colon cancer cells treated with camptothecin" 77 : 17154-17160, 2002

17 Pommier Y, "Repair of and checkpoint response to topoisomerase I-mediated DNA damage" 532 : 173-203, 2003

18 Wall ME, "Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from camptotheca acuminate" 88 : 3888-3890, 1966

19 Torres K, "Mechanisms of taxol-induced cell death are concentration dependent" 58 : 3620-3626, 1998

20 Giannakakou P, "Low concentrations of paclitaxel induce cell type-dependent p53, p21 and G1/G2 arrest instead of mitotic arrest: molecular determinants of paclitaxel-induced cytotoxicity" 20 : 3806-3813, 2001

21 Sinicrope FA, "Loss of p21WAF1/Cip1 protein expression accompanies progression of sporadic colorectal neoplasia but not hereditary nonpolyposis colorectal cancers" 4 : 1251-1261, 1998

22 Fuchs C, "Irinotecan in the treatment of colorectal cancer" 32 : 491-503, 2006

23 Downes CS, "Inhibitors of DNA topoisomerase II prevent chromatid separation in mammalian cells but do not prevent exit from mitosis" 88 : 8895-8899, 1991

24 Gupta M, "Inactivation of p53 increases the cytotoxicity of camptothecin in human colon HCT116 and breast MCF-7 cancer cells" 3 : 1653-1660, 1997

25 Liebmann J, "In vitro studies of taxol as a radiation sensitizer in human tumor cells" 86 : 441-446, 1994

26 Borbe R, "Failure of taxol-based combination chemotherapy for malignant glioma cannot be overcome by G2/M checkpoint abrogators or altering the p53 status" 44 : 217-227, 1999

27 Segal NH, "Evolving treatment of advanced colon cancer" 60 : 207-219, 2009

28 Abal M, "Enhanced sensitivity to irinotecan by Cdk1 inhibition in the p53-deficient HT29 human colon cancer cell line" 23 : 1737-1744, 2004

29 Satou M, "Enhanced sensitivity to cis-diamminedichloro-pla tinum(II) of a human carcinoma cell line with mutated p53 gene by cyclin-dependent kinase inhibitor p21WAF1 expression" 94 : 286-291, 2003

30 Kaufmann SH, "Cytotoxic effects of topotecan combined with various anticancer agents in human cancer cell lines" 88 : 734-741, 1996

31 Jemal A, "Cancer statistics" 58 : 71-96, 2008

32 Fishman AD, "Advances in the treatment of metastatic colorectal cancer" 1 : 20-35, 2001

33 Bathe OF, "A phase II experience with neoadjuvant irinotecan (CPT-11), 5-fluorouracil (5-FU) and leucovorin (LV) for color ectal liver metastases" 9 : 156-, 2009