Chemotherapeutic activity of silymarin combined with doxorubicin or paclitaxel in sensitive and multidrug-resistant colon cancer cells.
OBJECTIVE
The milk thistle extract silymarin, alone or in combined chemotherapy, is now under investigation in anticancer research, with particular interest for its possible employ in the treatment of chemoresistant tumours. So far, the consequences of a silymarin pre-treatment have not been thoroughly investigated. We studied whether silymarin pre-treatment synergized with chemotherapy, exploring the dose-dependence of the interaction in sensitive and multidrug-resistant cells.


METHODS
We studied cell cycle perturbations induced by silymarin in two colon carcinoma cell lines, LoVo and the multidrug-resistant isogenic LoVo/DX. Synergism/additivity/antagonism of silymarin-doxorubicin silymarin-paclitaxel combined treatments were evaluated by isobologram/combination index analysis, in the whole spectrum of active and sub-active concentrations of all drugs. The mechanisms of silymarin interaction with the other drugs were investigated by measuring drug uptake and cell cycle perturbations.


RESULTS
Silymarin had similar antiproliferative activity against both cell lines. Pre-treatment with low silymarin concentrations synergised with both doxorubicin and paclitaxel in LoVo but not in LoVo/DX. Higher silymarin concentrations were additive with doxorubicin and paclitaxel in both cell lines. Silymarin favourably interfered with uptake and cell cycle effects of the chemotherapeutics in LoVo but not in LoVo/DX.


CONCLUSIONS
These findings confirm activity of silymarin against colon carcinoma, including multidrug-resistant types, at relatively high but clinically achievable concentrations. In view of its low toxicity, two schedules based on low- and high-dose silymarin pre-treatment might offer a valuable option for combined treatment.
Colombo
Valentina
V
Laboratory of Anticancer Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milan, Italy.
Lupi
Monica
M
Falcetta
Francesca
F
Forestieri
Daniele
D
D'Incalci
Maurizio
M
Ubezio
Paolo
P
D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D004336:Drug Antagonism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology*; D012838:Silymarin / Q000494:pharmacology*
D012838:Silymarin; D004317:Doxorubicin; D017239:Paclitaxel