TY - JOUR
T1 - Collateral sensitivity as a strategy against cancer multidrug resistance
AU - Pluchino, Kristen M.
AU - Hall, Matthew D.
AU - Goldsborough, Andrew S.
AU - Callaghan, Richard
AU - Gottesman, Michael M.
PY - 2012
Y1 - 2012
N2 - While chemotherapy remains the most effective treatment for disseminated tumors, acquired or intrinsic drug resistance accounts for approximately 90% of treatment failure. Multidrug resistance (MDR), the simultaneous resistance to drugs that differ both structurally and mechanistically, often results from drug efflux pumps in the cell membrane that reduce intracellular drug levels to less than therapeutic concentrations. Expression of the MDR transporter P-glycoprotein (P-gp, MDR1, ABCB1) has been shown to correlate with overall poor chemotherapy response and prognosis. This review will focus on collateral sensitivity (CS), the ability of compounds to kill MDR cells selectively over the parental cells from which they were derived. Insights into CS may offer an alternative strategy for the clinical resolution of MDR, as highly selective and potent CS agents may lead to drugs that are effective at MDR cell killing and tumor resensitization. Four main mechanistic hypotheses for CS will be reviewed, followed by a discussion on quantitative and experimental evaluation of CS.
AB - While chemotherapy remains the most effective treatment for disseminated tumors, acquired or intrinsic drug resistance accounts for approximately 90% of treatment failure. Multidrug resistance (MDR), the simultaneous resistance to drugs that differ both structurally and mechanistically, often results from drug efflux pumps in the cell membrane that reduce intracellular drug levels to less than therapeutic concentrations. Expression of the MDR transporter P-glycoprotein (P-gp, MDR1, ABCB1) has been shown to correlate with overall poor chemotherapy response and prognosis. This review will focus on collateral sensitivity (CS), the ability of compounds to kill MDR cells selectively over the parental cells from which they were derived. Insights into CS may offer an alternative strategy for the clinical resolution of MDR, as highly selective and potent CS agents may lead to drugs that are effective at MDR cell killing and tumor resensitization. Four main mechanistic hypotheses for CS will be reviewed, followed by a discussion on quantitative and experimental evaluation of CS.
KW - Collateral sensitivity
KW - MDR1-selective
KW - MRP1
KW - Multidrug resistance
KW - P-glycoprotein
KW - Verapamil
UR - http://www.scopus.com/inward/record.url?scp=84860671176&partnerID=8YFLogxK
U2 - 10.1016/j.drup.2012.03.002
DO - 10.1016/j.drup.2012.03.002
M3 - Article
SN - 1368-7646
VL - 15
SP - 98
EP - 105
JO - Drug Resistance Updates
JF - Drug Resistance Updates
IS - 1-2
ER -