Overadditive anti-proliferative and pro-apoptotic effects of a combination therapy on colorectal carcinoma cells.
The prognosis of advanced colorectal carcinoma (CC) is poor. Established chemotherapy shows only limited efficacy but significant side effects. We investigated how far a combination of tamoxifen (TAM), 9-cis-retinoic acid (CRA) and the fluoroquinolone ciprofloxacin (CIP) synergize to inhibit proliferation and promote apoptosis of CC cells in vitro. The CC cell lines LOVO, CC-531 and SW-403 were incubated with TAM, CRA and CIP (10(minus;4)-10(minus;6) M) as single agents and in combination. Cell proliferation was assessed by bromodeoxyuridin incorporation. Apoptosis was quantified immunohistochemically and by FACS analysis after staining with propidium iodide. Changes in the expression of caspase 3, bax, bcl-2 and p21cip/waf were assessed by quantitative Western blotting. CRA and TAM monotherapy was moderately effective. Their combination enhanced apoptosis from 60% to more than 80% in all cell types. Apoptosis was paralleled by inhibition of proliferation and further potentiated by addition of CIP. The combination effectively up-regulated caspase 3 and bax and down-regulated bcl-2 and p21cip/waf. Combinations of biomodulaters act synergistically to inhibit proliferation and promote apoptosis in CC cells. Due to their known safety profile, this justifies clinical trials for colorectal cancer using combinations of these biological response modifiers.
Herold
Christoph
C
Department of Internal Medicine I, University Erlangen-Nuernberg, Ullmenweg 18, D-91054 Erlangen, Germany. christoph.herold@med1.imed.uni-erlangen.de
Ganslmayer
M
M
Ocker
M
M
Blauberger
S
S
Zopf
S
S
Hahn
E G
EG
Schuppan
D
D
D000077556:Alitretinoin; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy*; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis; D002455:Cell Division; D045744:Cell Line, Tumor; D002469:Cell Separation; D002939:Ciprofloxacin / Q000008:administration & dosage; D003110:Colonic Neoplasms / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007202:Indicators and Reagents / Q000494:pharmacology; D007700:Kinetics; D011379:Prognosis; D011419:Propidium / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D013629:Tamoxifen / Q000008:administration & dosage; D013997:Time Factors; D014212:Tretinoin / Q000008:administration & dosage; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D007202:Indicators and Reagents; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D013629:Tamoxifen; D000077556:Alitretinoin; D011419:Propidium; D014212:Tretinoin; D002939:Ciprofloxacin; D004247:DNA; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D001973:Bromodeoxyuridine