Suppression of ErbB-2 in androgen-independent human prostate cancer cells enhances cytotoxic effect by gemcitabine in an androgen-reduced environment.
We examined the efficacy of combination treatments utilizing cytotoxic drugs plus inhibitors to members of the ErbB-ERK signal pathway in human prostate cancer (PCa) LNCaP C-81 cells. Under an androgen-reduced condition, 50nM gemcitabine caused about 40% growth suppression on C-81 cells. Simultaneous treatment of gemcitabine plus 10microM AG825 produced 60% suppression (p<0.03); while, 85% growth inhibition (p<0.02) was seen if AG825 was added to gemcitabine-treated cells after a 24h-interval. Our data thus showed that in androgen-reduced conditions, inhibition of ErbB-2 increases the cytotoxic efficacy of gemcitabine in PCa cells. This finding has significant implications in the choice of drugs for combination therapy as well as the order of administration for treating cancer patients.
Zhang
Li
L
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, 68198-5870, USA.
Davis
Jeffrey S
JS
Zelivianski
Stanislav
S
Lin
Fen-Fen
FF
Schutte
Rachel
R
Davis
Thomas L
TL
Hauke
Ralph
R
Batra
Surinder K
SK
Lin
Ming-Fong
MF
D000728:Androgens / Q000172:deficiency / Q000378:metabolism*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D052160:Benzothiazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D020032:Tyrphostins / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism; D000093542:Gemcitabine
D000728:Androgens; D000964:Antimetabolites, Antineoplastic; D052160:Benzothiazoles; D003841:Deoxycytidine; D048049:Extracellular Signal-Regulated MAP Kinases; D005419:Flavonoids; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020032:Tyrphostins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D000093542:Gemcitabine; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C098214:tyrphostin AG825; C101044:RTKI cpd; C508053:ERBB2 protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one