Int J Biochem Mol Biol 2011;2(2):155-167
Original Article
Infection of H69AR cells with retroviral particles harboring interfering RNAi significantly
reduced the multidrug resistance of these small cell lung cancer cells

Kanagaraj Palaniyandi, Qing Zhao, Xiu-bao Chang

College of Medicine, Mayo Clinic - Mayo Clinic Arizona, Scottsdale, AZ 85259, USA.

Received April 8, 2011; accepted April 20, 2011; Epub April 22, 2011; Published April 30, 2011

Abstract: Incubation of the drug-sensitive H69, a small cell lung cancer cell line, with increased concentrations of adriamycin yielded multidrug
resistant (MDR) H69AR cells that overexpress multidrug resistance-associated protein (MRP1). MRP1 co-transports its substrate with
glutathione (GSH), leading to lower intracellular GSH. In this report we tested whether depleting intracellular GSH in MRP1-expressing cells
could hyper-sensitize them to anticancer drugs or not. We have found that the GSH contents in MRP1-expressing cells are significantly lower
than their corresponding control cells. The treatment with MRP1 substrate verapamil or the GSH synthetase inhibitor buthionine sulfoximine
significantly reduced the intracellular GSH contents in MRP1-expressing cells. Interestingly, depleting intracellular GSH contents can
hyper-sensitize the MRP1-cDNA transfected BHK cells to daunomycin, but not the adriamycin-selected H69AR cells. Further analyses indicated
that anti-apoptotic factor Bcl2 might be a factor responsible for the fact that depleting intracellular GSH could not hyper-sensitize H69AR cells to
daunomycin. We hypothesized that knocking down the expression of Bcl2 could hyper-sensitize H69AR cells to daunomycin. Interestingly,
infection of H69AR cells with retroviral particles harboring Bcl2 interfering RNAi not only reduced the expression of Bcl2, but also many factors
that contribute to MDR, such as Bcl-xL, MRP1 and ABCC3, etc., leading to the MDR H69AR cells more sensitive to daunomycin than the
parental H69 cell. Thus, although the mechanisms of the down-regulation of the genes contributing to MDR remain to be elucidated, retroviral
particles harboring Bcl2 interfering RNAi could be used as an alternative way to sensitize the MDR cancer cells to anticancer drugs.
(IJBMB1104002).

Keywords:

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Address all correspondence to:
Dr. Xiu-bao Chang
College of Medicine, Mayo Clinic
Mayo Clinic Arizona, Scottsdale
AZ 85259, USA.
E-mail:
xbchang@mayo.edu
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