Abstract
BackgroundColorectal cancer (CRC) is the third major cause of cancer related deaths in the world. 5-fluorouracil (5-FU) is widely used for the treatment of colorectal cancer but as a single-agent renders low response rates. Choline kinase alpha (ChoKα), an enzyme that plays a role in cell proliferation and transformation, has been reported overexpressed in many different tumors, including colorectal tumors. ChoKα inhibitors have recently entered clinical trials as a novel antitumor strategy.Methodology/Principal FindingsChoKα specific inhibitors, MN58b and TCD-717, have demonstrated a potent antitumoral activity both in vitro and in vivo against several tumor-derived cell line xenografts including CRC-derived cell lines. The effect of ChoKα inhibitors in combination with 5-FU as a new alternative for the treatment of colon tumors has been investigated both in vitro in CRC-tumour derived cell lines, and in vivo in mouse xenografts models. The effects on thymidilate synthase (TS) and thymidine kinase (TK1) levels, two enzymes known to play an essential role in the mechanism of action of 5-FU, were analyzed by western blotting and quantitative PCR analysis. The combination of 5-FU with ChoKα inhibitors resulted in a synergistic effect in vitro in three different human colon cancer cell lines, and in vivo against human colon xenografts in nude mice. ChoKα inhibitors modulate the expression levels of TS and TK1 through inhibition of E2F production, providing a rational for its mechanism of action.Conclusion/SignificanceOur data suggest that both drugs in combination display a synergistic antitumoral effect due to ChoKα inhibitors-driven modulation of the metabolization of 5-FU. The clinical relevance of these findings is strongly supported since TCD-717 has recently entered Phase I clinical trials against solid tumors.
Highlights
Colorectal cancer (CRC) is the first most prevalent cancer and is the second cause of cancer death in Europe with about 212.000 deaths every year [1]
Choline kinase alpha (ChoKa) levels were analyzed in the three colon cancer cell lines used in this study, DLD-1, HT29 and SW620 versus a non tumoral colorectal cell line CCD-841
This result is in keeping with previous analysis of ChoKa expression in tumor samples compared with matched normal tissues from the same patient [11], and provides a rational for the potential use of ChoKa inhibitors in the clinic in combination with standard chemotherapy
Summary
Colorectal cancer (CRC) is the first most prevalent cancer and is the second cause of cancer death in Europe with about 212.000 deaths every year [1]. Response rates for 5-FU based chemotherapy as a first-line treatment for advanced CRC cancer are only 10–15%. Combination of 5-FU with new cytotoxic drugs such as oxaliplatin and irinotecan has improved the response rates to 40– 50% [6,7]. Novel biological agents such as the monoclonal antibodies cetuximab and bevacizumab have demonstrated additional benefits in patients with metastatic disease [8,9]. This approach is achieving important improvements, and promotes new therapeutic strategies based on combinatorial treatments. 5-fluorouracil (5-FU) is widely used for the treatment of colorectal cancer but as a single-agent renders low response rates. ChoKa inhibitors have recently entered clinical trials as a novel antitumor strategy
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