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Chemotherapeutic activity of silymarin combined with doxorubicin or paclitaxel in sensitive and multidrug-resistant colon cancer cells

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Abstract

Purpose

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.

Conclusion

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.

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Acknowledgments

The generous contribution of the Italian Association for Cancer Research and the Nerina and Mario Mattioli Foundation is gratefully acknowledged.

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Authors and Affiliations

  1. Laboratory of Anticancer Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche “Mario Negri”, Via La Masa 19, 20156, Milan, Italy

    Valentina Colombo, Monica Lupi, Francesca Falcetta, Daniele Forestieri, Maurizio D’Incalci & Paolo Ubezio

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  1. Valentina Colombo
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  2. Monica Lupi
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  6. Paolo Ubezio
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Correspondence to Paolo Ubezio.

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Colombo, V., Lupi, M., Falcetta, F. et al. Chemotherapeutic activity of silymarin combined with doxorubicin or paclitaxel in sensitive and multidrug-resistant colon cancer cells. Cancer Chemother Pharmacol 67, 369–379 (2011). https://doi.org/10.1007/s00280-010-1335-8

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  • DOI: https://doi.org/10.1007/s00280-010-1335-8

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