Potential therapeutic targets of Guggulsterone in cancer

Abstract

Natural compounds capable of inducing apoptosis in cancer cells have always been of considerable interest as potential anti-cancer agents. Many such compounds are under screening and development with their potential evolution as a clinical drug benefiting many of the cancer patients. Guggulsterone (GS), a phytosterol isolated gum resin of the tree Commiphora mukul has been widely used in Indian traditional medicine as a remedy for various diseses. GS has been shown to possess cancer chemopreventive and therapeutic potential as established by in vitro and in vivo studies. GS has been shown to target constitutively activated survival pathways such as PI3-kinase/AKT, JAK/STAT, and NFκB signaling pathways that are involved in the regulation of growth and inflammatory responses via regulation of antiapoptotic and inflammatory genes. The current review focuses on the molecular targets of GS, cellular responses, and the animal model studies in various cancers. The mechanistic action of GS in different types of cancers also forms a part of this review. The perspective of translating this natural compound into a clinically approved drug with its pros and cons is also discussed.

Keywords: Cancers; Chemoprevention; Guggulsterone; Molecular targets; Natural compounds.

Fig. 1

a The Plant Commiphora mukul. The chemical structure of Guggulsterone isoforms, E-Guggulsterone (b) and Z-Guggulsterone (c)

Fig. 2

Biochemical and molecular targets of Guggulsterone. Guggulsterone exerts anti-cancer effects through activation or suppression of protein kinases, transcription factors, anti-oxidant enzymes, cell cycle regulators, proapoptotic and antiapoptotic proteins. GS exerts anti-inflammatory effects through suppression of nuclear factor-kB (NF-kB), which plays a crucial role in the inflammatory processes by regulating the expression of diverse proinflammatory proteins, including cyclooxygenase-2 (COX-2). GS fortifies cellular defense against oxidative stress by inducing the de novo synthesis of the powerful antioxidant enzyme heme oxygenase-1 (HO-1). GS induces apoptosis by increasing the expression of proapoptotic proteins while decreasing the levels of antiapoptotic proteins (e.g., IAP1, XIAP, Bfl-1/A1, Bcl-2, cFLIP, Survivin, etc.). GS induces apoptosis by increasing the expression of proapoptotic proteins while decreasing the levels of antiapoptotic proteins (e.g., IAP1, XIAP, Bfl-1/A1, Bcl-2, cFLIP, Survivin, etc.). GS suppresses invasion and metastasis by targeting MMPs, FXR etc

Fig. 3

Schematic diagram illustrating the main biological targets of Guggulsterone. The apoptotic effects of guggulsterone are preceded by activation of JNK, suppression of Akt and NF-kB activity. Activation of JNK leads to induction of propapoptic proteins and release of cytochrome c from the mitochondria which in turn activates caspases, resulting in apoptosis. Down regulation of NF-kB activity leads to inhibition of anti apoptotic proteins which in turn activates caspases, resulting in apoptosis and inhibition of proliferation

Fig. 4

Schematic representation of Guggulsterone mediated effects on various biological processes. i) Abrogating pro-inflammatory signaling by inhibiting activity/expression of IKK-NF-kB, STAT3, COX-2,iNOS, etc. ii) Inhibition of cancer cell proliferation through cell cycle arrest by modulating cyclins, CDKs, etc. iii) Induction of apoptosis of cancerous or transformed cells by modulating expression/activity of caspases, IAPs, Bcl-2 family proteins, etc. iv) Inhibition of angiogenesis by targeting HIF-1a, VEGF, VEGF-R, etc. v) Sensitization of tumor cells to apoptosis induced by chemotherapeutic drugs and reversal of multidrug resistance