E1A-mediated paclitaxel sensitization in HER-2/neu-overexpressing ovarian cancer SKOV3.ip1 through apoptosis involving the caspase-3 pathway.
HER-2/neu-overexpressing breast cancer cells are more resistant to the chemotherapeutic agent paclitaxel (Taxol) than low-HER-2/neu-expressing breast cancer cells, and the adenoviral type 5 EIA can down-regulate HER-2/neu overexpression. Therefore, in this study, we asked (a) whether EIA might sensitize response to paclitaxel in human HER-2/neu-overexpressing ovarian cancer cells, and, if so, what is the mechanism responsible; and (b) whether this enhanced chemosensitivity would translate into a therapeutic effect in an ovarian cancer xenograft model. Consequently, we demonstrated that: (a) adenovirus type 5 E1A could enhance the sensitivity of paclitaxel in paclitaxel-resistant HER-2/neu-overexpressing human ovarian cancer cells in vitro by inducing apoptosis, (b) this induction was heavily dependent on activation of the caspase-3 pathway, and (c) nude mice bearing i.p. HER-2/neu-overexpressing human ovarian cancer cells and treated with both paclitaxel and E1A gene therapy survived significantly longer than did mice treated only with paclitaxel or E1A gene therapy. Thus, we concluded that the E1A gene enhanced both the in vitro and in vivo sensitivity of paclitaxel in paclitaxel-resistant HER-2/ neu-overexpressing ovarian cancer SKOV3.ipl cells. Because a Phase I clinical trial using E1A gene targeted to HER-2/neu down-regulation has recently been completed, the current study also provided a scientific basis to further develop a novel therapy that combines paclitaxel and E1A gene therapy and its testing in a Phase II trial.
Ueno
N T
NT
Department of Blood and Marrow Transplantation, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Bartholomeusz
C
C
Herrmann
J L
JL
Estrov
Z
Z
Shao
R
R
Andreeff
M
M
Price
J
J
Paul
R W
RW
Anklesaria
P
P
Yu
D
D
Hung
M C
MC
D017500:Adenovirus E1A Proteins / Q000235:genetics* / Q000378:metabolism; D000260:Adenoviruses, Human / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy*; D017239:Paclitaxel / Q000627:therapeutic use* / Q000633:toxicity*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D013534:Survival; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D017500:Adenovirus E1A Proteins; D053148:Caspase 3; D020169:Caspases; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse