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Published on: January 11, 2019
Effect of MDR1 phosphorothioate antisense oligodeoxynucleotides in multidrug-resistant human tumor cell lines and
Cheppail Ramachandran1, Larry L Wellham
1Department of Radiation Oncology, University of Miami School of Medicine, Research Institute, Miami, Children's Hospital, Miami, FL, USA. cheppail.ramachandran@mch.com
Abstract:
The effect of MDR1 antisense phosphorothiate oligodeoxynucleotides (S-ODNs) on resistant phenotype was investigated in multidrug-resistant human colon carcinoma and breast carcinoma cells in vitro and in vivo. Drug resistance in human colon carcinoma (SW620 Ad300) and breast carcinoma (MCF-7/INT500, MCF-7/AD150 and MCF-7/TH) cell lines is predominantly due to overexpression of P-glycoprotein (P-gp) resulting in decreased daunorubicin (DNR) accumulation. Two MDR1 antisense S-ODNs, one complementary to the initial 15 bases of first exon (S-ODN I) and the other a loop forming sequence (S-ODN II) complementary to bases from 993-1007 of MDR1 gene, were tested for enhancing the doxorubicin (DOX) cytotoxicity in vitro and the efficiency of chemotherapy in human tumor xenografts. MDR1 antisense S-ODN I reduced the DOX IC50 value 9-fold in multidrug-resistant SW620 Ad300 human colon carcinoma cells and 7 to 10-fold in breast carcinoma cells in vitro. The increase in DOX cytotoxicity correlated with a significant reduction of MDR1 mRNA in antisense S-ODN I-treated SW620 Ad300 cells. Even though the P-gp level was reduced at the end of the third day in antisense S-ODN I-treated cells, the rate of reduction was only partial compared to mRNA. The combination treatment of MDR1 antisense S-ODN I or II for three days and DOX for four days significantly controlled tumor growth rate in human tumors developed in nude mice. Our results suggest that MDR1 antisense S-ODN treatment can increase the efficiency of chemotherapy by suppressing gene expression and resistant phenotype.
Insights
MDR1 antisense oligodeoxynucleotides (S-ODNs) effectively resensitize multidrug-resistant cancer cells to chemotherapy. This approach enhances doxorubicin efficacy by suppressing MDR1 gene expression and P-glycoprotein levels, improving tumor treatment outcomes.
Area of Science:
- Molecular Biology
- Pharmacology
- Oncology
Background:
- Multidrug resistance (MDR) in cancer, particularly in colon and breast carcinoma, is often mediated by P-glycoprotein (P-gp) overexpression.
- P-gp efflux pumps reduce intracellular accumulation of chemotherapeutic agents like doxorubicin, leading to treatment failure.
Purpose of the Study:
- To investigate the efficacy of MDR1 antisense phosphorothioate oligodeoxynucleotides (S-ODNs) in overcoming MDR in human colon and breast cancer cells.
- To evaluate the impact of MDR1 antisense S-ODNs on doxorubicin (DOX) cytotoxicity in vitro and in vivo chemotherapy efficiency.
Main Methods:
- Utilized two MDR1 antisense S-ODNs (S-ODN I and S-ODN II) targeting the MDR1 gene.
- Assessed DOX cytotoxicity and MDR1 mRNA/P-gp levels in resistant cell lines (SW620 Ad300, MCF-7 variants) in vitro.
- Evaluated the combination therapy of S-ODNs and DOX in human tumor xenografts in nude mice.
Main Results:
- MDR1 antisense S-ODN I significantly reduced DOX IC50 values by 9-fold in colon cancer cells and 7-10 fold in breast cancer cells.
- Treatment with S-ODN I led to a substantial decrease in MDR1 mRNA levels and a partial reduction in P-gp levels.
- Combined S-ODN and DOX treatment effectively controlled tumor growth in vivo xenograft models.
Conclusions:
- MDR1 antisense S-ODNs show promise in reversing multidrug resistance by suppressing MDR1 gene expression.
- This strategy can enhance the efficacy of chemotherapy, offering a potential new avenue for treating resistant cancers.
- Antisense oligodeoxynucleotide therapy represents a viable approach to improve chemotherapeutic outcomes in resistant malignancies.
