Effect of retinoic acid and interferon alpha-2a on transitional cell carcinoma of bladder.
OBJECTIVE
Retinoids modulate the growth and differentiation of normal and malignant epithelial cells in vitro and in vivo. Retinoids and their analogues have been used in animal models and clinical trials of chemoprevention and superficial bladder cancer treatment. Interferons are cytokines that have antiviral, antiproliferative and immunomodulatory function. They are used in many clinical trials for the treatment of different cancers. To identify new effective agents and develop novel approaches for the chemoprevention and treatment of superficial bladder cancer we investigated the effects of a combination of retinoids and interferon alpha-2a (IFN) on growth and apoptosis in bladder cancer cell lines.


METHODS
The 4 bladder cancer cell lines UM-UC-6, UM-UC-9, UM-UC-10 and UM-UC-13 were treated with 2 retinoids, namely all-trans-retinoic acid (ATRA) and 9-cis retinoic acid (9cRA), as well as with IFN or with combinations of retinoids and IFN. The ability of these agents used alone and in combination to inhibit growth, induce apoptosis and modulate gene expression was investigated. The effects of retinoids on an INF related gene were also examined.


RESULTS
Most bladder cancer cell lines were resistant to growth inhibition and apoptosis induction by ATRA and 9cRA, even at a high concentration. The effects of these retinoids on cell growth and apoptosis were enhanced by IFN. The combination of ATRA and IFN induced retinoic acid receptor beta, and signal transducer and activator of transcription 1 expression in 3 bladder cancer cell lines, as detected by reverse transcriptase-polymerase chain reaction and Western blot analysis. Retinoids increased IFN-related gene expression detected by microarray analysis and real-time reverse transcriptase-polymerase chain reaction.


CONCLUSIONS
The results demonstrate that IFN acts synergistically with ATRA and 9cRA in the growth and apoptosis of bladder cancer cells in vitro and suggest that this combination has a potential for the treatment of transitional cell carcinoma of the bladder.
Zou
Changping
C
Department of Obstetrics/Gynecology and Urology, University of Arizona, Tucson, Arizona 85724, USA.
Ramakumar
Sanjay
S
Qian
Lixin
L
Zou
Changchun
C
Zang
Rongyu
R
Wang
Jian
J
Grossman
H Barton
HB
Lotan
Reuben
R
Liebert
Monica
M
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D004359:Drug Therapy, Combination; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D040081:Protein Array Analysis; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014212:Tretinoin / Q000627:therapeutic use*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D014212:Tretinoin