Cancer: Leukemia, cervical cancer
Action: MDR
Guggulsterones are isolated from Commiphora wightii [(Arn.) Bhandari].
Leukemia
The anti-leukemic effects of three isomeric pregnadienedione steroids, cis-guggulsterone, trans-guggulsterone, and 16-dehydroprogesterone, were investigated in HL60 and U937 cells as well as in primary leukemic blasts in culture. Results showed that all three compounds inhibited the proliferation of HL60 and U937 cells, with IC50s ranging from 3.6 to 10.9 µmol/L after treatment for 6 days. These growth-inhibitory effects correlated with externalization of phosphatidylserine and loss of mitochondrial membrane potential., suggesting that these isomeric steroids induce apoptosis in leukemia cells. z-VAD-fmk prevented phosphatidylserine externalization but not mitochondrial membrane potential loss, indicating that mitochondrial dysfunction occurred in the absence of caspase activation.
Interestingly, although all three compounds increased the generation of reactive oxygen species and decreased phosphorylation of extracellular signal-regulated kinase, only cis-guggulsterone induced a rapid depletion of reduced glutathione levels and oxidation of the mitochondrial phospholipid cardiolipin.
Guggulsterones and 16-dehydroprogesterone hence exert anti-leukemic effects via the induction of apoptosis and differentiation and, more importantly, identifies the pregnadienedione structure as a potential chemotherapeutic scaffold (Samudio et al., 2005).
Multi-drug Resistance
Natural phytosterols, such as beta-sitosterol, campesterol, stigmasterol, fucosterol, and z-guggulsterone, are found in foods, herbs, and dietary supplements. The effects of dietary plant sterols on human drug efflux transporters P-glycoprotein (P-gp, ABCB1) and multi-drug resistance protein 1 (MRP1, ABCC1) were investigated using P-gp-overexpressing human carcinoma KB-C2 cells and human MRP1 gene-transfected KB/MRP cells.
The accumulation of daunorubicin or rhodamine 123, fluorescent substrates of P-gp, increased in the presence of guggulsterone in KB-C2 cells. The efflux of rhodamine 123 from KB-C2 cells was inhibited by guggulsterone. Guggulsterone also increased the accumulation of calcein, a fluorescent substrate of MRP1, in KB/MRP cells. The ATPase activities of P-gp and MRP1 were stimulated by guggulsterone.
These results suggest that guggulsterone, a natural dietary hypolipidemic agent, have dual inhibitory effects on P-gp and MRP1 and the potencies to cause food-drug interactions.
References