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Ecdysteroids reverse resistance of human mdr1 gene transfected mouse lymphoma cells
Multidrug resistance is a major health problem that affects cancer therapy. The use of compounds as adjuvants, with the potential to improve the effect of existing chemotherapeutics that have fallen by the wayside due to MDR, is a new approach for the therapy of MDR cancer. Ecdysteroids are steroidal hormones of the invertebrates. They are also frequently found in plants, where they are held to play an important defensive role against non-adapted herbivores. Ten ecdysteroids were tested for their cytotoxicity against L5178 mouse T-cell lymphoma cells transfected with pHa MDR1/A retrovirus (MDR) and its parental cell line (non MDR). The activity of the compounds as modulators of the efflux of rhodamine123 by the human ABCB1 pump (commonly known as P-gp) of the MDR cells was determined by flow cytometry. The compounds were also tested for their combination activity in presence of doxorubicin, a known substrate of the ABCB1 pump. It was observed that these of non-cytotoxic compounds showed modulation of the efflux activity by the ABCB1 pump. In combination with doxorubicin, it was observed a synergistic effect by the ecdysteroids and doxorubicin, with a decrease of the IC50 of doxorubicin. In the presence of 18µM of the 20-hydroxyecdysone 2,3,20,22-diacetonide, the IC50 of doxorubicin was reduced by ten times. Considering that ecdysteroids are of extremely low toxicity in vertebrates, including humans, and act as mild anabolics and adaptogenes, our findings may lead to the discovery of a potent adjuvant with a highly beneficial side-effect profile in the chemotherapy of MDR cancer.
Acknowledgements: This work was supported by Hungarian Research Fund (OTKA K72771) grant. The author thanks Dr. Imre Ocsovszki for the flow cytometry measurements.