Chemotherapy and Metabolic InhibitorsIn vitro and in vivo reversal of cancer cell multidrug resistance by the semi-synthetic antibiotic tiamulin
Section snippets
Chemicals
Cell culture media (Dulbecco’s modified Eagle’s medium and RPMI-1640) were from BioWhittaker and fetal bovine serum was from Sigma. ADR, COL, daunomycin, propidium iodide, antibiotic, and antimycotic solution (containing 10,000 units/mL of penicillin, 10 mg/mL of streptomycin, and 25 μg/mL of amphotericin B), were from Sigma. VBL was a gift from Roger Bellon Laboratories. Tiamulin (BM cyclin) was purchased from Boehringer Mannheim. All drugs were prepared in water under sterile conditions and
Tiamulin
Tiamulin (Fig. 1) or [3aS-(3aα,4β,5α,6α,8β,9α,9αβ,10S)]-[(2-(diethylamino)ethyl)thio]acetic acid 6-ethenyldecahydro-5hydroxy-4,6,9,10-tetramethyl-1-oxo-3a,9-propano-3aH-cyclopentacycloocten-8-yl ester] (C28H47NO4S, molecular weight 493.76) is a semi-synthetic derivative of the natural antibiotic pleuromutilin isolated from the Basidiomycete Pleurotus mutilus[13]. It is frequently used in veterinary medicine to treat Gram-positive and mycoplasma infections of farm animals and is known to have no
Discussion
The results reported in the present study strongly support the notion that tiamulin, a semi-synthetic antibiotic used against Gram positive and mycoplasma infections in farm animals, promotes anticancer drug accumulation and modulates Pgp activity in Pgp-expressing or Pgp-overexpressing multidrug-resistant cancer cells in vitro and in vivo.
Although a common chemical basis for the modulating action of all chemosensitizers does not seem to exist, several “rules” have been defined for the design
Acknowledgements
The authors wish to thank Annick Berne, Jacques Vigouroux, Isabelle Guilhot, Blandine Lermite, and Aurélien Menuet for their help in cell culture, and Christophe Tenin for scientific discussion. Vinblastine was a gift from Roger Bellon Laboratories. We also thank Dr. Laurence J. Miller at the Mayo Clinic for stimulating discussion and improving the English of the manuscript. This work was supported by grants from the Association pour la Recherche contre le Cancer (Grant 6756 to L.G.B.), from
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Natural alkaloids as P-gp inhibitors for multidrug resistance reversal in cancer
2017, European Journal of Medicinal ChemistryCitation Excerpt :Moreover, up on i.p. administration (1.6 mg/mg body weight), tiamulin increased the survival rate of DOX-treated mice bearing the P388/DOX25 tumor line by 29%. In the presence of an anticancer drug, tiamulin inhibited both ATPase (IC50 = 0.54 μM) and [3H]-VBL transport (IC50 = 6.2 μM) in plasma membranes from tumor cells [145]. N-Arachidonoyl-ethanolamide (104) an endogenous canabinoid, modulates the P-gp inhibition activity at moderate levels in HEK-293 cells.
Establishment and characterization of an MDCK cell line stably-transfected with chicken Abcb1 encoding P-glycoprotein
2016, Research in Veterinary ScienceCitation Excerpt :It is well known that tiamulin, a semi-synthetic pleuromutilin commonly used in the control of pulmonary infections in chicken, produces a lethal interaction with ionophoric drugs. Later it has been found that tiamulin is an inhibitor of P-gp in human and rodent cell lines (Baggetto et al., 1998), and salinomycin is a substrate of P-gp (Lagas et al., 2008). This has clarified the issue of the drug-drug interactions described between ionophores and pleuromutilins.
Modulating cancer multidrug resistance by sertraline in combination with a nanomedicine
2014, Cancer LettersCitation Excerpt :A combination treatment between DOX and sertraline slows down tumor growth in NAR xenograft mouse model (Fig. 3A) and increased the survival (Fig. 3B) by 1.5-fold. Bearing in mind the dose-related problems with previous-generation chemosensitizers, we deliberately set out to test, in vivo, a low sertraline dose: 2 mg/kg body/day compared (for example) to the ranges of 5 to 30, 2 to 8, and 200 to 300 mg/kg body/dose for OC144–093, XR9756 and MS-209 respectively [22,34–36]. For treatment of depression, sertraline is prescribed at the dose range of 50–100 mg/person/day [37].
Implications of ABC transporters on the disposition of typical veterinary medicinal products
2008, European Journal of PharmacologyCitation Excerpt :It is well known to produce clinically important and often lethal interactions with ionophoric drugs, particularly the coccidiostats monensin and salinomycin, resulting in an increased cardiomyotoxicity as a common sign of ionophore toxicity (Ratz et al., 1997; Szucs et al., 2004). Tiamulin has later been identified as an inhibitor of P-gp in human and rodent cell lines (Baggetto et al., 1998) and is thus a potential inhibitor of P-gp in farm animal species. The recent finding that salinomycin is a P-gp substrate, suggests that the drug–drug interactions described between ionophores and pleuromutilins are not only related to inhibition of biotransformation, but also to inhibition of P-gp.
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Present address: Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, MN 55905, U.S.A.