摘要
Multidrug resistance(MDR)develops during chemotherapy in nearly all colorectal cancerpatients.It is envisaged that reversal of MDR plays a pivotal role in the success of chemotherapy.This study investigated thepotential pharmacological action in reversing MDR in colon cancer cells by the two most potent tanshinones,namely cryptotanshinone and dihydrotanshinone.They targeted two common MDR mechanisms,including overexpression of P-glycoprotein(P-gp)and suppression of apoptosis.Using a bi-directional transport assay,the two tanshinones decreased P-gp-mediated digoxin effluxin Caco-2 cells.They also potentiated the cytotoxicities of doxorubicin and irinotecan in P-gp overexpressing SW620Ad300 cells via increased intracellular accumulation of both anti-cancer drugs,as a result of down-regulation of P-gp mRNA and protein levels as well as inhibition of P-gp ATPase activity.In addition,the level of apoptosis was also found to be relatively suppressed in SW620Ad300 cells as compared with the parental SW620 cells.Interestingly,although cryptotanshinone and dihydrotanshinone induced less apoptosis in SW620Ad300 cells as compared to their parental cells,they produced more autophagic cell death in these MDR cells.In this regard,the drug resistant SW620Ad300 cells were more prone to cell death in response to the anti-cancer action of thetwo tanshinones.Furthermore,the cytotoxic action of the two tanshinones was shown to be p53-independent,further demonstrated theirunique anti-cancer activities in overcoming drug resistance due to the reduction of p53 expression together with a decrease of apoptosis in colon cancer cells.Taken together,the current findings indicate a great potential for cryptotanshinone and dihydrotanshinone against MDR colon cancer cells,in spite of P-gp overexpression and suppression of apoptosis.They are promising candidates to be developed as therapeutic agents and/or as an adjuvant therapy for colorectal cancer,especially for patients with MDR cancer types.
Multidrug resistance(MDR)develops during chemotherapy in nearly all colorectal cancerpatients.It is envisaged that reversal of MDR plays a pivotal role in the success of chemotherapy.This study investigated thepotential pharmacological action in reversing MDR in colon cancer cells by the two most potent tanshinones,namely cryptotanshinone and dihydrotanshinone.They targeted two common MDR mechanisms,including overexpression of P-glycoprotein(P-gp)and suppression of apoptosis.Using a bi-directional transport assay,the two tanshinones decreased P-gp-mediated digoxin effluxin Caco-2 cells.They also potentiated the cytotoxicities of doxorubicin and irinotecan in P-gp overexpressing SW620Ad300 cells via increased intracellular accumulation of both anti-cancer drugs,as a result of down-regulation of P-gp mRNA and protein levels as well as inhibition of P-gp ATPase activity.In addition,the level of apoptosis was also found to be relatively suppressed in SW620Ad300 cells as compared with the parental SW620 cells.Interestingly,although cryptotanshinone and dihydrotanshinone induced less apoptosis in SW620Ad300 cells as compared to their parental cells,they produced more autophagic cell death in these MDR cells.In this regard,the drug resistant SW620Ad300 cells were more prone to cell death in response to the anti-cancer action of thetwo tanshinones.Furthermore,the cytotoxic action of the two tanshinones was shown to be p53-independent,further demonstrated theirunique anti-cancer activities in overcoming drug resistance due to the reduction of p53 expression together with a decrease of apoptosis in colon cancer cells.Taken together,the current findings indicate a great potential for cryptotanshinone and dihydrotanshinone against MDR colon cancer cells,in spite of P-gp overexpression and suppression of apoptosis.They are promising candidates to be developed as therapeutic agents and/or as an adjuvant therapy for colorectal cancer,especially for patients with MDR cancer types.
出处
《中国药理学与毒理学杂志》
CAS
CSCD
北大核心
2015年第S1期8-8,共1页
Chinese Journal of Pharmacology and Toxicology
基金
The project supported by the Hong Kong Research Grants Council and the Innovation Technology Commission
