Changes in P-glycoprotein activity are mediated by the growth of a tumour cell line as multicellular spheroids

Cancer Cell International

Barrera-Rodríguez Raúl¹  Ponce de León Valeria¹ 

[1] Depto. de Bioquímica. Instituto Nacional de Enfermedades Respiratorias-SSA México. Clza. Tlalpan, 4502, C.P. 14080, México, D.F

关键词: NSCLC;    Multicellular drug resistance;    Multicellular spheroids;    P-Glycoprotein;   

Others  :  795991
DOI  :  10.1186/1475-2867-5-20

 received in 2005-03-29, accepted in 2005-07-07,  发布年份 2005

【 摘 要 】

Background

Expression of P-glycoprotein (P-gp), the multidrug resistance (MDR) 1 gene product, can lead to multidrug resistance in tumours. However, the physiological role of P-gp in tumours growing as multicellular spheroids is not well understood. Recent evidence suggests that P-gp activity may be modulated by cellular components such as membrane proteins, membrane-anchoring proteins or membrane-lipid composition. Since, multicellular spheroids studies have evidenced alterations in numerous cellular components, including those related to the plasma membrane function, result plausible that some of these changes might modulate P-gp function and be responsible for the acquisition of multicellular drug resistance. In the present study, we asked if a human lung cancer cell line (INER-51) grown as multicellular spheroids can modify the P-gp activity to decrease the levels of doxorubicin (DXR) retained and increase their drug resistance.

Results

Our results showed that INER-51 spheroids retain 3-folds lower doxorubicin than the same cells as monolayers however; differences in retention were not observed when the P-gp substrate Rho-123 was used. Interestingly, neither the use of the P-gp-modulating agent cyclosporin-A (Cs-A) nor a decrease in ATP-pools were able to increase DXR retention in the multicellular spheroids. Only the lack of P-gp expression throughout the pharmacological selection of a P-gp negative (P-gp^neg) mutant clone (PSC-1) derived from INER-51 cells, allow increase of DXR retention in spheroids.

Conclusion

Thus, multicellular arrangement appears to alter the P-gp activity to maintain lower levels of DXR. However, the non expression of P-gp by cells forming multicellular spheroids has only a minor impact in the resistance to chemotherapeutic agents.

【 授权许可】

   
2005 Valeria and Raúl; licensee BioMed Central Ltd.

【 图 表 】

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