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DOI: 10.1055/s-0034-1394788
Combination effect of ecdysteroid 2,3-dioxalanes and doxorubicin against MDR resistant cancer
Over-expressed efflux pumps of cancer cells frequently contribute to the failure of cancer chemotherapy. These proteins are responsible for the extrusion of a large variety of unrelated chemically distinct compounds that are toxic to the cell. Hence their increased presence leads to a multi-drug resistant (MDR) phenotype. Ecdysteroids are analogues of insect hormones that occur in plants. These compounds are not recognized by human steroid receptors. Some mild beneficial bioactivities have been described and have led to the worldwide marketing of ecdysteroid containing food supplements. Previously we found that some ecdysteroids increased the activity of doxorubicin against an MDR mouse lymphoma cell line over-expressing the human ABCB1 [1,2]. The observed structure activity relationships (SARs) highlighted the importance of apolar groups at positions 2,3 [2]. In our present work we have further explored relevant SAR by investigating a number of compounds bearing a substituted dioxolane ring at the 2,3 position of the steroidal A-ring. Two mouse lymphoma cell lines were used in this work: a parental (PAR) cell line, L5178 mouse T-cell lymphoma cells; and a multi-drug resistant (MDR) cell line derived from PAR by transfection with pHa MDR1/A retrovirus. It was observed that in general the 2,3-dioxolanes were less cytotoxic than their equivalent 20,22-substituted analogues, but exerted a much stronger sensitizing effect on the MDR cell line to doxorubicin. Due to their negligible in vitro cytotoxity at the active concentrations, these compounds are promising MDR modulators. In vivo bioactivities and possible future therapeutic relevance against MDR cancer are under investigation.
Acknowledgements: The authors acknowledge the Szeged Foundation for Cancer Research; the European Union and the European Social Fund: TÁMOP 4.2.2.A-11/1/KONV-2012 – 0035; and the Fundação para a Ciência e a Tecnologia: PEst-OE/SAU/UI0074/2011, PEst-OE/SAU/UI0074/2014, SFRH/BPD/81118/2011.
Keywords: Multi-drug resistance, ecdysteroids, combination therapy, ABCB1, MDR1, Pgp
References:
[1] Martins A, Tóth N, Ványolós A, Béni Z, Zupkó I, Molnár J, Báthori M, Hunyadi A. Significant activity of ecdysteroids on the resistance to doxorubicin in mammalian cancer cells expressing the human ABCB1 transporter. J Med Chem 2012; 55 (11): 5034 – 5043.
[2] Martins A, Csábi J. Kitka D. Balázs A. Amaral L. Molnár J. Simon A. Tóth G. Hunyadi A. Synthesis and Structure-Activity Relationship Study of Novel Ecdysteroid Dioxolanes as MDR Modulators in Cancer. Molecules 2013; 18(12): 15255 – 15275.