Reversal of P-Glycoprotein-Mediated Drug Efflux by Eudesmin from Haplophyllum perforatum and Cytotoxicity Pattern versus Diphyllin, Podophyllotoxin and Etoposide

Abstract

The present study focuses on eudesmin (bicyclic lignan, 0.15 % of dry leaves) and diphyllin (arylnaphthalene lignan, 0.1 % of dry roots), both isolated from H. perforatum Kar. et Kir, a Rutaceae species endemic to Uzbekistan. We first compared their specificity for cancer cells with those of etoposide and podophyllotoxin by screening their cytotoxicity on 3 healthy cell-lines and 7 sensitive or resistant human solid cancer lines. We then tested their capacity to reverse P-glycoprotein-mediated multidrug resistance (MDR) by assaying dye and drug uptake in MDR1-transfected Madin-Darby canine kidney (MDCK-MDR1) and doxorubicine-resistant human breast carcinoma cells (MCF7/Dox). Eudesmin displays IC (50) values > 100 microM on all tested lines. Our data provide the first demonstration that this non-toxic lignan reverses Pgp-mediated drug efflux and supports the hypothesis that it may inhibit resistance mediated by MDR1 and MRP proteins. Even if its reversal activity is insufficient for clinical application, its capacity to accumulate [(3)H]-vinblastine in MDCK/MDR1 and MCF7/Dox cells suggests that eudesmin may positively affect the bioavailability and, thereby, the therapeutic potency of anticancer drugs in Pgp-overexpressing cells. Diphyllin exhibits IC (50) values ranging from 10 (- 6) to 10 (- 4) M. It is markedly less toxic than podophyllotoxin (IC (50) : 13 - 61 nM), but exhibits tumoricidal effects close to those of etoposide. Unfortunatly, it is 65-fold more toxic than etoposide on human primary fibroblasts. Consequently, it has no value as an anticancer drug. Its value as raw material for the hemisynthesis of anticancer drugs is discussed.

CHEMICAL CHARACTERIZATION OF LIGNANS FROM Araucaria araucana A NATIVE CONIFER OF CHILE AND EVALUATION OF THEIR CYTOTOXICITY AND ANTIOXIDANT ACTIVITIES

“…Extracts of stemwood, branchwood, knotwood, and all isolated compounds were evaluated for their cytotoxicity and antioxidant bioassays. In the cytotoxic analysis of eudesmin, it did not give positive cytotoxic activity in SHSY5Y and P3X cells., In comparison to other studies in PC3 (Prostate carcinoma), MCF (Breast carcinoma), PA1 (Ovary carcinoma), DLD1 (Colon carcinoma), or M4Beu (Malignant melanoma) [26], that showed that eudesmin possesses significant antitumor effects on lung cancer A549 (IC50 18.3 uM) via to induction of mitochondria-mediated apoptosis [27], as well as in nasopharyngeal carcinoma cells eudesmin inhibited cell viability and induced apoptosis of NPC cells [28]. However, the cytotoxic activity is not fully understanding, could be suggested that eudesmin is high specific against some particular cancer cell lines; this deserves more in-depth studies and could become a potential cancer-fighting drug.…”

Differential modulation of Bax/Bcl-2 ratio and onset of caspase-3/7 activation induced by derivatives of Justicidin B in human melanoma cells A375

“…Previous reports pointed towards Diphillyn as a substrate of P-glycoprotein (MDR1/P-gp) [ 7 ], thus potentially limiting its therapeutic potential. This prompted us to test their in vitro cytotoxicity on the melanoma cell line SK-Mel-5, reported to be one of the melanoma lineages expressing higher levels of the ABCB1 transcript [ 22 ], both alone and in the presence of non toxic concentrations of verapamil, a known Pgp inhibitor widely used in cancer research [ 23 ].…”

“…Later on, the authors claimed that Diphyllin itself have no value as anti-cancer drug, first because its negative cytotoxic index -high tocixicity on both cancer and human primary cells. Modern studies pointed that its anti-proliferative action on cancer cells may involve the cell cycle arrest in the S-phase and inhibition of protein synthesis [ 5 ] but also cytotoxic activity towards human monocytes and skin tissues [ 6 ] and that it is effluxed by P-glycoprotein (P-gp) [ 7 ], thus limiting its therapeutic potential. However, glycosilation may revert the negative cytotoxic index as in the case podophyllotoxin/etoposide.…”

Transcriptomics-Based Repositioning of Natural Compound, Eudesmin, as a PRC2 Modulator

“…Although many studies have reported many therapeutic effects of eudesmin, such as anti-tumor [ 12 , 13 ], anti-fungal [ 14 ], anti-bacterial [ 15 ], and anti-inflammatory [ 16 ] effects, the genomewide analysis in which eudesmin controls multiple sets of genes has not been performed. In this study, we elucidated that eudesmin modulates the expression of PRC2 target genes through comprehensive transcriptomic analysis of our RNA-sequencing data and Enrichr ( Figure 1 A).…”