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Modulation of multidrug resistance by cepharanthine in fresh human gastrointestinal tumor cells
T Hotta1, H Tanimura, H Yamaue
1Second Department of Surgery, Wakayama Medical School, Japan.
Abstract:
Resistance to doxorubicin (DOX) is mainly due to the effect of P-glycoprotein encoded by the multidrug resistance (MDR) gene. Cepharanthine (CEP) has been shown to circumvent multidrug resistance in P-glycoprotein-expressing cell lines. In the present study, we investigated the augmentation of DOX sensitivity by CEP using an MTT assay, and assessed the correlation between DOX sensitivity and P-glycoprotein expression by flow cytometry, in highly purified fresh human tumor cells obtained from 73 cancer patients. DOX sensitivity was decreased in proportion to P-glycoprotein expression. The cytotoxicity of DOX was increased by CEP in tumor cells possessing low DOX sensitivity. Moreover, there was a significant correlation between the effect of CEP on cytotoxicity and P-glycoprotein expression. Thus, CEP might be able to circumvent DOX resistance in cancer patients.
Insights
Cepharanthine (CEP) may overcome doxorubicin (DOX) resistance in cancer by reducing P-glycoprotein expression. This study found CEP increased DOX sensitivity in tumor cells with low sensitivity, suggesting a potential therapeutic strategy.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Doxorubicin (DOX) resistance is a major challenge in cancer therapy, often mediated by P-glycoprotein (P-gp) efflux pumps.
- P-glycoprotein, encoded by the multidrug resistance (MDR) gene, actively transports DOX out of cancer cells, reducing its efficacy.
- Cepharanthine (CEP) has demonstrated potential in overcoming multidrug resistance in preclinical models.
Purpose of the Study:
- To investigate if Cepharanthine (CEP) can enhance the sensitivity of human tumor cells to Doxorubicin (DOX).
- To assess the correlation between P-glycoprotein expression levels and DOX sensitivity in patient-derived tumor cells.
- To determine if CEP's effect on cytotoxicity is linked to P-glycoprotein expression.
Main Methods:
- Utilized MTT assays to quantify the cytotoxicity of DOX and CEP in human tumor cells.
- Employed flow cytometry to measure P-glycoprotein expression in purified tumor cells from 73 cancer patients.
- Analyzed the relationship between P-glycoprotein levels, DOX sensitivity, and the impact of CEP.
Main Results:
- DOX sensitivity inversely correlated with P-glycoprotein expression levels in human tumor cells.
- CEP significantly increased the cytotoxicity of DOX in tumor cells exhibiting low initial DOX sensitivity.
- A significant correlation was observed between CEP's augmentation of cytotoxicity and the level of P-glycoprotein expression.
Conclusions:
- Cepharanthine (CEP) shows promise in circumventing Doxorubicin (DOX) resistance mediated by P-glycoprotein.
- CEP may represent a viable therapeutic agent to restore DOX efficacy in resistant cancers.
- The study highlights the potential of targeting P-glycoprotein with CEP in clinical oncology settings.