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A search for multidrug resistance modulators: the effects of retinoids in human colon carcinoma cells
G Bartolini1, M Orlandi, A Papi
1Department of Experimental Evolutive Biology, University of Bologna, Italy.
Abstract:
The development of multidrug resistance (MDR) is one of the major causes of failure in cancer therapy. The use of cell lines with acquired resistance to anticancer agents represents a very good tool for investigation into the possibility of reversal of MDR. In this study the ability of all-trans-retinoic acid (RA) and its derivative 6-OH-11-O-hydroxyphenanthrene (IIF; pat. WIPO W000 /117143) as antitumor agents was investigated in the human colon carcinoma cell line LoVo and in the counterpart resistant derivative LoVo/MDR cell line. Cell proliferation was measured by MTT assay, apoptosis was evaluated using DNA fragmentation and Annexin V detection assay. Retinoids suppressed cell proliferation in a time- and dose-dependent manner. Interestingly, IIF was significantly more effective than RA, particularly on LoVo/MDR cells. RA and IIF induced apoptosis in both cell lines, with IIF effect significantly higher than that of RA. Furthermore, on the basis that MDR phenotype is often caused by drug efflux due to overexpression of the membrane P-glycoprotein (P-gp), it was demonstrated that RA and IIF reduced P-gp synthesis in LoVo/MDR cells. Our results suggest that IIF could be a powerful tool in the development of colon carcinoma treatments, even when tumor cells present an MDR phenotype.
Insights
A novel retinoid derivative, IIF, effectively combats multidrug resistance (MDR) in colon cancer cells. IIF suppresses cancer cell proliferation and induces apoptosis, offering a promising therapeutic strategy for MDR tumors.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Multidrug resistance (MDR) significantly hinders cancer treatment efficacy.
- Cell lines with acquired resistance are crucial for studying MDR reversal.
- P-glycoprotein (P-gp) overexpression is a common mechanism of MDR.
Purpose of the Study:
- To investigate the antitumor potential of all-trans-retinoic acid (RA) and its derivative IIF.
- To evaluate their efficacy in both drug-sensitive (LoVo) and multidrug-resistant (LoVo/MDR) colon carcinoma cell lines.
- To determine if RA and IIF can overcome MDR by targeting P-gp.
Main Methods:
- Cell proliferation assessed via MTT assay.
- Apoptosis evaluated using DNA fragmentation and Annexin V assays.
- P-glycoprotein (P-gp) synthesis levels measured in LoVo/MDR cells.
Main Results:
- Both RA and IIF inhibited cell proliferation in a time- and dose-dependent manner.
- IIF demonstrated superior efficacy compared to RA, especially in LoVo/MDR cells.
- RA and IIF induced apoptosis, with IIF showing a more pronounced effect.
- IIF and RA reduced P-gp synthesis in LoVo/MDR cells, suggesting MDR reversal.
Conclusions:
- IIF exhibits significant antitumor activity against colon carcinoma cells, including MDR variants.
- IIF effectively suppresses proliferation, induces apoptosis, and reduces P-gp expression.
- IIF represents a promising therapeutic agent for colon cancer treatment, even in the presence of MDR.
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