Synergistic interaction between tetra-arsenic oxide and paclitaxel in human cancer cells in vitro.
Similar to arsenic trioxide (As2O3), tetra-arsenic oxide (As4O6, TAO) has shown anti-proliferative and apoptosis-inducing effects against human leukemic and solid tumor cells. In order to assess the increase in efficacy, we evaluated the combinatory interaction of TAO combined with paclitaxel, 5-FU or cisplatin and studied its mechanism of action in the cell lines of human gastric, cervix and head and neck tumors. Two agents were combined at equitoxic ratios based on the IC50 of each drug. Efficacy improvement was evaluated using a combination index and isobologram at 50% inhibition level. Apoptosis induction and expression of apoptosis-related proteins was determined and the effect on microtubule polymerization was monitored. TAO combined with paclitaxel showed synergistic interaction in all three of gastric, cervix and head and neck cancer cell lines. On the other hand, TAO when combined with 5-FU or cisplatin showed an antagonistic interaction in head and neck or cervix cancer cell lines, respectively. Simultaneous treatment with TAO with paclitaxel resulted in an increased percentage of apoptotic cells and a significant increase in PARP cleavage and caspase-3 activation in the gastric and cervix cancer cells compared to TAO alone as well as the antagonistic groups (TAO with 5-FU or cisplatin). TAO suppressed the tubulin polymerization in the presence and absence of paclitaxel in a concentration-dependent manner, suggesting mitotic catastrophe as a potential mechanism of the synergism with paclitaxel. Overall, the present study suggests that TAO may have a greater potential as an anti-cancer agent against human gastric, cervix and head and neck tumors, in combination with paclitaxel. The synergistic interaction with paclitaxel may be associated with increased apoptosis via inhibition of paclitaxel-induced tubulin polymerization. Further detailed studies of combinatory mechanisms and evaluation using in vivo models are warranted.
Department of Biomedical Sciences, College of Medicine, The Catholic University of Korea, Seocho-ku, Seoul 137-401, Korea.
Won-Heui
WH
Chung
Bong Hwan
BH
Sung
Sang-Soo
SS
Kim
Hyangshuk
H
Rhim
Hyo-Jeong
HJ
Kuh
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage; D004347:Drug Interactions; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D010087:Oxides / Q000008:administration & dosage; D017239:Paclitaxel / Q000008:administration & dosage; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D001152:Arsenicals; C494826:BAX protein, human; D010087:Oxides; C495901:TP53 protein, human; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D017239:Paclitaxel; D002945:Cisplatin; D000077237:Arsenic Trioxide; D005472:Fluorouracil