Development of Ad-mda7/IL-24-resistant lung cancer cell lines

Abujiang Pataer; Sunil Chada; Jack A. Roth; Kelly K. Hunt; Stephen G. Swisher

doi:10.4161/cbt.7.1.5162

Development of Ad-mda7/IL-24-resistant lung cancer cell lines

Abujiang Pataer, Sunil Chada, Jack A. Roth, Kelly K. Hunt, Stephen G. Swisher

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

Many cancers can become resistant to repeated administration of even the most effective therapeutic agents. In developing adenoviral mda-7/IL-24 (Ad-mda-7/IL-24) therapy for lung cancer, we have anticipated this potential clinical problem by attempting to identify the molecular mechanisms of Ad-mda7/IL-24 resistance in several Ad-mda7/IL-24-resistant lung cancer cell lines that we have developed. For the present study, we established four Admda7-resistant cell lines by repeated selection of resistant clones of parental Ad-mda7-sensitive A549 cells: two lines (A549R1 and A549R2) resistant to both adenoviral vector and the mda-7 gene and two (A549R3 and A549R4) resistant to the therapeutic mda-7 gene only. As shown by western blot analysis of several known anti-apoptotic proteins, parental A549 and resistant A549R3 cells expressed similar levels of AKT and phosphorylated AKT (p-AKT), whereas resistant A549R3 and A549R4 cells expressed higher levels of bcl-2 and lower levels of bcl-xL than did their parental cells. As shown by flow-cytometric analysis, treating resistant A549R3 and A549R4 cells with a combination of Ad-mda7 and 17-allylamino-17-demethoxygeldanamycin (17AAG) (50 nM) for 48 hours enhanced apoptosis. Together, these in vitro findings indicate that an antiapoptotic mechanism may underlie Ad-mda7 resistance and that such resistance can be overcome by addition of 17AAG. Further investigations along these lines are warranted.

Original language	English (US)
Pages (from-to)	103-108
Number of pages	6
Journal	Cancer Biology and Therapy
Volume	7
Issue number	1
DOIs	https://doi.org/10.4161/cbt.7.1.5162
State	Published - Jan 2008

Keywords

Adenovirus
Apoptosis
Gene therapy
MDA-7
Resistant cell lines

ASJC Scopus subject areas

Molecular Medicine
Oncology
Pharmacology
Cancer Research

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@article{177cfc72dd5d4eed86b32d06f81fc85e,

title = "Development of Ad-mda7/IL-24-resistant lung cancer cell lines",

abstract = "Many cancers can become resistant to repeated administration of even the most effective therapeutic agents. In developing adenoviral mda-7/IL-24 (Ad-mda-7/IL-24) therapy for lung cancer, we have anticipated this potential clinical problem by attempting to identify the molecular mechanisms of Ad-mda7/IL-24 resistance in several Ad-mda7/IL-24-resistant lung cancer cell lines that we have developed. For the present study, we established four Admda7-resistant cell lines by repeated selection of resistant clones of parental Ad-mda7-sensitive A549 cells: two lines (A549R1 and A549R2) resistant to both adenoviral vector and the mda-7 gene and two (A549R3 and A549R4) resistant to the therapeutic mda-7 gene only. As shown by western blot analysis of several known anti-apoptotic proteins, parental A549 and resistant A549R3 cells expressed similar levels of AKT and phosphorylated AKT (p-AKT), whereas resistant A549R3 and A549R4 cells expressed higher levels of bcl-2 and lower levels of bcl-xL than did their parental cells. As shown by flow-cytometric analysis, treating resistant A549R3 and A549R4 cells with a combination of Ad-mda7 and 17-allylamino-17-demethoxygeldanamycin (17AAG) (50 nM) for 48 hours enhanced apoptosis. Together, these in vitro findings indicate that an antiapoptotic mechanism may underlie Ad-mda7 resistance and that such resistance can be overcome by addition of 17AAG. Further investigations along these lines are warranted.",

keywords = "Adenovirus, Apoptosis, Gene therapy, MDA-7, Resistant cell lines",

author = "Abujiang Pataer and Sunil Chada and Roth, {Jack A.} and Hunt, {Kelly K.} and Swisher, {Stephen G.}",

note = "Funding Information: Grant support National Cancer Institute and National Institutes of Health grants P01 CA78778‑01A1 (J.A. Roth and S.G. Swisher), SPORE 2P50‑CA70970‑04, SBIR S/C 1R43 CA86587‑1 (S.G. Swisher and S. Chada), and supporting Core Grant CA16672 (M. D. Anderson Cancer Center); gifts from Tenneco and Exxon to the Division of Surgery for its Core Laboratory Facility; donations from the Charles Rogers Memorial and Gene Therapy Donor funds; a grant from the Tobacco Settlement Funds as appropriated by the Texas State Legislature (Project 8); a grant from the W. M. Keck Foundation; and a sponsored research agreement with Introgen Therapeutics, Inc. (SR93‑004‑1). (Grant support from the Homer Flower Gene Therapy Fund, the Charles Rogers Gene Therapy Fund and the George P. Sweeney Esophageal Research Fund.)",

year = "2008",

month = jan,

doi = "10.4161/cbt.7.1.5162",

language = "English (US)",

volume = "7",

pages = "103--108",

journal = "Cancer Biology and Therapy",

issn = "1538-4047",

publisher = "Landes Bioscience",

number = "1",

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TY - JOUR

T1 - Development of Ad-mda7/IL-24-resistant lung cancer cell lines

AU - Pataer, Abujiang

AU - Chada, Sunil

AU - Roth, Jack A.

AU - Hunt, Kelly K.

AU - Swisher, Stephen G.

N1 - Funding Information: Grant support National Cancer Institute and National Institutes of Health grants P01 CA78778‑01A1 (J.A. Roth and S.G. Swisher), SPORE 2P50‑CA70970‑04, SBIR S/C 1R43 CA86587‑1 (S.G. Swisher and S. Chada), and supporting Core Grant CA16672 (M. D. Anderson Cancer Center); gifts from Tenneco and Exxon to the Division of Surgery for its Core Laboratory Facility; donations from the Charles Rogers Memorial and Gene Therapy Donor funds; a grant from the Tobacco Settlement Funds as appropriated by the Texas State Legislature (Project 8); a grant from the W. M. Keck Foundation; and a sponsored research agreement with Introgen Therapeutics, Inc. (SR93‑004‑1). (Grant support from the Homer Flower Gene Therapy Fund, the Charles Rogers Gene Therapy Fund and the George P. Sweeney Esophageal Research Fund.)

PY - 2008/1

Y1 - 2008/1

N2 - Many cancers can become resistant to repeated administration of even the most effective therapeutic agents. In developing adenoviral mda-7/IL-24 (Ad-mda-7/IL-24) therapy for lung cancer, we have anticipated this potential clinical problem by attempting to identify the molecular mechanisms of Ad-mda7/IL-24 resistance in several Ad-mda7/IL-24-resistant lung cancer cell lines that we have developed. For the present study, we established four Admda7-resistant cell lines by repeated selection of resistant clones of parental Ad-mda7-sensitive A549 cells: two lines (A549R1 and A549R2) resistant to both adenoviral vector and the mda-7 gene and two (A549R3 and A549R4) resistant to the therapeutic mda-7 gene only. As shown by western blot analysis of several known anti-apoptotic proteins, parental A549 and resistant A549R3 cells expressed similar levels of AKT and phosphorylated AKT (p-AKT), whereas resistant A549R3 and A549R4 cells expressed higher levels of bcl-2 and lower levels of bcl-xL than did their parental cells. As shown by flow-cytometric analysis, treating resistant A549R3 and A549R4 cells with a combination of Ad-mda7 and 17-allylamino-17-demethoxygeldanamycin (17AAG) (50 nM) for 48 hours enhanced apoptosis. Together, these in vitro findings indicate that an antiapoptotic mechanism may underlie Ad-mda7 resistance and that such resistance can be overcome by addition of 17AAG. Further investigations along these lines are warranted.

AB - Many cancers can become resistant to repeated administration of even the most effective therapeutic agents. In developing adenoviral mda-7/IL-24 (Ad-mda-7/IL-24) therapy for lung cancer, we have anticipated this potential clinical problem by attempting to identify the molecular mechanisms of Ad-mda7/IL-24 resistance in several Ad-mda7/IL-24-resistant lung cancer cell lines that we have developed. For the present study, we established four Admda7-resistant cell lines by repeated selection of resistant clones of parental Ad-mda7-sensitive A549 cells: two lines (A549R1 and A549R2) resistant to both adenoviral vector and the mda-7 gene and two (A549R3 and A549R4) resistant to the therapeutic mda-7 gene only. As shown by western blot analysis of several known anti-apoptotic proteins, parental A549 and resistant A549R3 cells expressed similar levels of AKT and phosphorylated AKT (p-AKT), whereas resistant A549R3 and A549R4 cells expressed higher levels of bcl-2 and lower levels of bcl-xL than did their parental cells. As shown by flow-cytometric analysis, treating resistant A549R3 and A549R4 cells with a combination of Ad-mda7 and 17-allylamino-17-demethoxygeldanamycin (17AAG) (50 nM) for 48 hours enhanced apoptosis. Together, these in vitro findings indicate that an antiapoptotic mechanism may underlie Ad-mda7 resistance and that such resistance can be overcome by addition of 17AAG. Further investigations along these lines are warranted.

KW - Adenovirus

KW - Apoptosis

KW - Gene therapy

KW - MDA-7

KW - Resistant cell lines

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JO - Cancer Biology and Therapy

JF - Cancer Biology and Therapy

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ER -

Development of Ad-mda7/IL-24-resistant lung cancer cell lines

Abstract

Keywords

ASJC Scopus subject areas

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