The recent article by Frankenberg et al. about how the membrane protein adenosine triphosphatase class I type 8B member 1 signals through protein kinase C zeta to activate the farnesoid X receptor (FXR) was highly though-provoking and fascinating.1 The authors have clearly illustrated the important role of FXRs in human physiology and pathology. Modulation of FXR function has been in focus recently, and an interesting new antagonist (guggulsterone) has been identified in this regards. The potential role of guggulsterone in clinical medicine has been highlighted by recent studies that have demonstrated its beneficial effects in diseases ranging from systemic malignancies to morbid obesity.
For instance, guggulsterone has an antiproliferative effect not just on dermatologic malignancies2 such as malignant melanomas but also on a myriad number of other localized malignancies such as breast carcinomas as well as a number of systemic hematological malignancies such as leukemias.3 These antiproliferative effects are in part due to the inhibition of tumor angiogenesis.4 Guggulsterone also effectively and remarkably induces apoptosis in cell lines derived from Barrett's esophagitis. In fact, guggulsterone attenuates the expression of the FXR secondary to stimulation by bile acids in subjects with Barrett's esophagitis.5 Barrett's esophagitis is a precursor of esophageal adenocarcinoma and this inhibitory effect may have a major role to play in the near future in cancer chemoprevention in patients with Barrett's esophagitis.6 Guggulsterone performs these functions by the suppression of nuclear factor-kappa B activation as well as signal transducer and activator of transcription 3 (STAT3) activation7 in tissues ranging from myeloma cells to pancreatic tissue.8
Besides anticarcinogenic properties, guggulsterone also has highly beneficial cardiovascular effects as a result of its anti-inflammatory and hypolipidemic properties9 and also prevents cytokine-mediated cytotoxicity in pancreatic beta cells.8 Guggulsterone also inhibits differentiation of adipocytes and may thus have a potential role in weight loss.10 Similarly, Lee et al. have recently shown that guggulsterone also blocks interleukin-1beta–mediated inflammatory responses in synoviocytes.11 The data from all these studies support the rapidly expanding evidence in support of the anti-inflammatory properties of guggulsterone.
Clearly, guggulsterone may very well prove to be a major tool in the hands of physicians and oncologists in the fight against various systemic cancers as well as diseases such as obesity in the near future.