Preclinical study of treatment response in HCT-116 cells and xenografts with 1H-decoupled 31P MRS Journal Article
| Authors: | Darpolor, M. M.; Kennealey, P. T.; Le, H. C.; Zakian, K. L.; Ackerstaff, E.; Rizwan, A.; Chen, J. H.; Sambol, E. B.; Schwartz, G. K.; Singer, S.; Koutcher, J. A. |
| Article Title: | Preclinical study of treatment response in HCT-116 cells and xenografts with 1H-decoupled 31P MRS |
| Abstract: | The topoisomerase I inhibitor, irinotecan, and its active metabolite SN-38 have been shown to induce G2/M cell cycle arrest without significant cell death in human colon carcinoma cells (HCT-116). Subsequent treatment of these G2/M-arrested cells with the cyclin-dependent kinase inhibitor, flavopiridol, induced these cells to undergo apoptosis. The goal of this study was to develop a noninvasive metabolic biomarker for early tumor response and target inhibition of irinotecan followed by flavopiridol treatment in a longitudinal study. A total of eleven mice bearing HCT-116 xenografts were separated into two cohorts where one cohort was administered saline and the other treated with a sequential course of irinotecan followed by flavopiridol. Each mouse xenograft was longitudinally monitored with proton (1H)-decoupled phosphorus (31P) magnetic resonance spectroscopy (MRS) before and after treatment. A statistically significant decrease in phosphocholine (p=0.0004) and inorganic phosphate (p=0.0103) levels were observed in HCT-116 xenografts following treatment, which were evidenced within twenty-four hours of treatment completion. Also, a significant growth delay was found in treated xenografts. To discern the underlying mechanism for the treatment response of the xenografts, in vitro HCT-116 cell cultures were investigated with enzymatic assays, cell cycle analysis, and apoptotic assays. Flavopiridol had a direct effect on choline kinase as measured by a 67% reduction in the phosphorylation of choline to phosphocholine. Cells treated with SN-38 alone underwent 83±5% G2/M cell cycle arrest compared to untreated cells. In cells, flavopiridol alone induced 5±1% apoptosis while the sequential treatment (SN-38 then flavopiridol) resulted in 39±10% apoptosis. In vivo 1H-decoupled 31P MRS indirectly measures choline kinase activity. The decrease in phosphocholine may be a potential indicator of early tumor response to the sequential treatment of irinotecan followed by flavopiridol in noninvasive and/or longitudinal studies. Copyright © 2011 John Wiley & Sons, Ltd. In vivo 1H-decoupled 31P MRS indirectly measures choline kinase activity by the decrease in phosphocholine that may be a potential indicator of early tumor response to the sequential treatment of irinotecan followed by flavopiridol in longitudinal study. Results indicate that irinotecan facilitates G2/M HCT-116 cells arrest, and a follow-up treatment with flavopiridol induces these G2/M-arrested cells to synergistically undergo apoptosis. © 2011 John Wiley & Sons, Ltd. |
| Keywords: | apoptosis; irinotecan; colon cancer; flavopiridol; choline kinase; 1h-decoupled 31p mrs |
| Journal Title: | NMR in Biomedicine |
| Volume: | 24 |
| Issue: | 9 |
| ISSN: | 0952-3480 |
| Publisher: | John Wiley & Sons |
| Date Published: | 2011-11-01 |
| Start Page: | 1159 |
| End Page: | 1168 |
| Language: | English |
| DOI: | 10.1002/nbm.1674 |
| PROVIDER: | scopus |
| PMCID: | PMC3201722 |
| PUBMED: | 21994185 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 2 November 2011" - "CODEN: NMRBE" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work