pregna-4-17-diene-3-16-dione and Neoplasms

Guggulsterone [4, 17(20)-pregnadiene-3, 16-dione] is a plant sterol derived from the gum resin of the tree Commiphora wightii. The gum resin of the guggul tree has been used in traditional medicine for centuries to treat obesity, liver disorders, internal tumors, malignant sores, ulcers, urinary complaints, intestinal worms, leucoderma, sinus, edema and sudden paralytic seizures. Guggulsterone has been shown to modulate the nuclear receptors, farnesoid X receptor, pregnane X receptor, CYP 2b10 gene expression, and the bile salt export pump for cholesterol elimination. Recent research indicates that the active components of gum guggul, E- and Zguggulsterone have the potential to both prevent and treat cancers. Guggulsterone inhibits the growth of a wide variety of tumor cells and induces apoptosis through down regulation of antiapoptotic gene products (IAP1, xIAP, Bfl-1/A1, Bcl-2, cFLIP, and survivin), modulation of cell cycle proteins (cyclin D1 and c-Myc), activation of caspases, inhibition of Akt, and activation of JNK. Guggulsterone modulates the expression of gene products involved in metastasis (MMP-9, COX-2, and VEGF) of tumor cells. Guggulsterone mediates gene expression through the modulation of several transcription factors, including NF-κB, STAT3, C/EBPα, androgen receptor, and glucocorticoid receptors. This review describes the anti-cancer properties, molecular targets, and the apoptotic effects of guggulsterone.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Commiphora; Humans; Molecular Structure; Neoplasms; Neovascularization, Pathologic; Plant Gums; Pregnenediones; Resins, Plant; Xenograft Model Antitumor Assays

Guggulsterone (GS) is a phytosterol derived from the gum resin of guggul plants that have been used traditionally to treat various disorders such as burns, wounds, gastric ulcer, cough, gum diseases, urinary complaints, diarrhea, stomach cramps, fascioliasis, and intestinal worms. It has anti-inflammatory and antioxidative properties and has recently attracted substantial attention due to its cancer chemopreventive and therapeutic potential exemplified by its antiproliferative, antimetastatic, and proapoptotic properties in many cancer cell lines and animal models. This review highlights some of the cancer chemopreventive/therapeutic targets of GS and the underlying molecular mechanisms.

Topics: Humans; Neoplasms; Pregnenediones; Signal Transduction

Parkinson's disease (PD), a common neurodegenerative disorder, results from the loss of motor function when dopaminergic neurons (DNs) in the brain selectively degenerate. While pluripotent stem cells (PSCs) show promise for generating replacement neurons, current protocols for generating terminally differentiated DNs require a complicated cocktail of factors. Recent work demonstrated that a naturally occurring steroid called guggulsterone effectively differentiated PSCs into DNs, simplifying this process. In this study, we encapsulated guggulsterone into novel poly-ε-caprolactone-based microspheres and characterized its release profile over 44 d in vitro, demonstrating we can control its release over time. These guggulsterone-releasing microspheres were also successfully incorporated in human induced pluripotent stem cell-derived cellular aggregates under feeder-free and xeno-free conditions and cultured for 20 d to determine their effect on differentiation. All cultures stained positive for the early neuronal marker TUJ1 and guggulsterone microsphere-incorporated aggregates did not adversely affect neurite length and branching. Guggulsterone microsphere incorporated aggregates exhibited the highest levels of TUJ1 expression as well as high Olig 2 expression, an inhibitor of the STAT3 astrogenesis pathway previously known as a target for guggulsterone in cancer treatment. Together, this study represents an important first step towards engineered neural tissues consisting of guggulsterone microspheres and PSCs for generating DNs that could eventually be evaluated in a pre-clinical model of PD.

Topics: Cell Culture Techniques; Cell Differentiation; Cell Transplantation; Cells, Cultured; Dopaminergic Neurons; Drug Delivery Systems; Humans; Induced Pluripotent Stem Cells; Microscopy, Fluorescence; Microspheres; Neoplasms; Neural Stem Cells; Neurogenesis; Particle Size; Pregnenediones

Guggulsterone is a plant polyphenol traditionally used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, possibly through an anti-inflammatory mechanism. Whether this steroid has any role in cancer is not known. In this study, we found that guggulsterone inhibits the proliferation of wide variety of human tumor cell types including leukemia, head and neck carcinoma, multiple myeloma, lung carcinoma, melanoma, breast carcinoma, and ovarian carcinoma. Guggulsterone also inhibited the proliferation of drug-resistant cancer cells (e.g., gleevac-resistant leukemia, dexamethasone-resistant multiple myeloma, and doxorubicin-resistant breast cancer cells). Guggulsterone suppressed the proliferation of cells through inhibition of DNA synthesis, producing cell cycle arrest in S-phase, and this arrest correlated with a decrease in the levels of cyclin D1 and cdc2 and a concomitant increase in the levels of cyclin-dependent kinase inhibitor p21 and p27. Guggulsterone-induced apoptosis as indicated by increase in the number of Annexin V- and TUNEL-positive cells, through the downregulation of anti-apoptototic products. The apoptosis induced by guggulsterone was also indicated by the activation of caspase-8, bid cleavage, cytochrome c release, caspase-9 activation, caspase-3 activation, and PARP cleavage. The apoptotic effects of guggulsterone were preceded by activation of JNK and downregulation of Akt activity. JNK was needed for guggulsterone-induced apoptosis, inasmuch as inhibition of JNK by pharmacological inhibitors or by genetic deletion of MKK4 (activator of JNK) abolished the activity. Overall, our results indicate that guggulsterone can inhibit cell proliferation and induce apoptosis through the activation of JNK, suppression of Akt, and downregulation of antiapoptotic protein expression.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Commiphora; DNA Replication; Down-Regulation; Drug Screening Assays, Antitumor; Female; Humans; JNK Mitogen-Activated Protein Kinases; Neoplasms; Pregnenediones; Proto-Oncogene Proteins c-akt; S Phase