Planta Med 2011; 77 - PM90
DOI: 10.1055/s-0031-1282848

New pentacyclic diterpene polyesters isolated from Euphorbia falcata L. as resistance modulators in cancer cells

A Martins 1, E Sulyok 1, A Vasas 1, J Molnár 2, J Hohmann 1
  • 1Institute of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Szeged Hungary
  • 2Institute of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged Hungary

Resistance is a major cause of failure of chemotherapy and efflux is one of its major mechanisms that render the cancer cell resistant to more than one anti-cancer agent. The use of adjuvants that restore the activity of already existing chemotherapeutics is a promising way to overcome resistance.

Four new premyrsinane- (1–4) and three cyclomyrsinane-type (5–7) diterpene polyesters isolated from E. falcata L. 1 were tested for their activity as efflux modulators. The compounds were identified as di- (1), tetra- (2), penta- (3), hexa- (4,5) and heptaester (6,7) derivatives of a polyfunctional diterpene alcohol, acylated with acetic, propanoic, isobutanoic, 2-methyl-butanoic, n-hexanoic and benzoic acids

Compounds 2, 3, 4, 6 and 7 increased the retention of rhodamine123 in L5178 mouse T-cell lymphoma cells transfected with pHa MDR1/A retrovirus2 yielding fluorescence activity ratios between 12.63 and 46.15at 0.002 mM. The compounds when used in combination with doxorubicin synergistically decreased resistance of the cells yielding combination index values at ED50 between 0.13 and 0.34 and at ED90 between 0.03 and 0.3.

Among premyrsinanes the presence of 7-OBz and 15-Ac groups seem to be important for the activity of the compounds. The acetyl group at position C-17 slightly decreases activity. In case of cyclomyrsinanes, compounds with benzoyl group have lower activity while lack of substitution at C-17 increases activity.

The results of this work contribute to the understanding of important structural elements of diterpene polyesters for the design of new effective compounds that may be used as adjuvants for therapy of multidrug resistant cancer.

Keywords: Diterpene polyesters, Resistance modulator, Cancer therapy, ABCB1, efflux pump

Acknowledgement: This work was supported by the Hungarian Research Fund (OTKA K72771), the New Hungary Development Plan (TÁMOP-4.2.2.-08/1–2008–0013 ad TÁMOP-4.2.1/B-09/1/KOV-2010–005) and the Szeged Foundation of Cancer Research. A. Vasas acknowledges to the János Bolyai Scholarship from the Hungarian Academy of Sciences.

References: 1. Sulyok E et al. (2010) Planta Med 76: 1257

2. Kars MD et al. (2006) Anticancer Research 26: 4559–4568.