Deoxyelephantopin and Isodeoxyelephantopin as Potential Anticancer Agents with Effects on Multiple Signaling Pathways

Abstract

Cancer is the 2nd leading cause of death worldwide. The development of drugs to target only one specific signaling pathway has limited therapeutic success. Developing chemotherapeutics to target multiple signaling pathways has emerged as a new prototype for cancer treatment. Deoxyelephantopin (DET) and isodeoxyelephantopin (IDET) are sesquiterpene lactone components of "Elephantopus scaber and Elephantopus carolinianus", traditional Chinese medicinal herbs that have long been used as folk medicines to treat liver diseases, diabetes, diuresis, bronchitis, fever, diarrhea, dysentery, cancer, and inflammation. Recently, the anticancer activity of DET and IDET has been widely investigated. Here, our aim is to review the current status of DET and IDET, and discuss their anticancer activity with specific emphasis on molecular targets and mechanisms used by these compounds to trigger apoptosis pathways which may help to further design and conduct research to develop them as lead therapeutic drugs for cancer treatments. The literature has shown that DET and IDET induce apoptosis through multiple signaling pathways which are deregulated in cancer cells and suggested that by targeting multiple pathways simultaneously, these compounds could selectively kill cancer cells. This review suggests that DET and IDET hold promising anticancer activity but additional studies and clinical trials are needed to validate and understand their therapeutic effect to develop them into potent therapeutics for the treatment of cancer.

Keywords: Elephantopus carolinianus; Elephantopus scaber; apoptosis; cancer; deoxyelephantopin; inflammation; isodeoxyelephantopin.

Figure 1

Chemical structure and natural sources of deoxyelephantopin (DET) and isodeoxyelephantopin (IDET).

Figure 2

A schematic representation of DET- and IDET-induced cell cycle arrest at multiple phases in different cancer cell lines. DET and IDET inhibit S phase and/or G2/M phase transition by down-regulating the expression of cyclin-dependent kinase 1 (CDK1), CDK2, CDK4, CDK6, cyclin A2, cyclin D1, cyclin D3, cyclin E2, cyclin B1, and cdc2 while up-regulating the expression of p21 (CDK inhibitor) and p53, a tumor suppresser gene which regulates cell cycle arrest at different phases by inducing p21;├ Inhibition, ↑ Up-regulation.

Figure 3

A schematic representation of DET- and IDET-induced apoptosis in different cancer cell lines. DET and IDET trigger the activation of extrinsic apoptosis by activating caspase-8 which in turn either initiates the type 1 extrinsic apoptotic pathway by activating downstream effector caspase-3 or the type 2 extrinsic apoptotic pathway by truncation of Bid. DET and IDET induce intrinsic apoptosis by dissipating mitochondrial membrane potential and modulating the expression of Bcl-2 family proteins which results in the activation of caspase-3. Subsequently, activated caspase-3 leads to apoptosis by substrate cleavage. DET activates c-Jun N-terminal kinase (JNK) and p38 and inhibits the activation of Phosphatidylinositol-3-Kinase (PI3K)/AKT/ mammalian target of rapamycin (mTOR). DET inhibits the activation of extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) and activates caspase-9 and induces apoptosis; ├ Inhibition, ↑ Up-regulation, ↓ Down-regulation.

Figure 4

Proposed mechanism by which DET and IDET inhibit nuclear factor kappa B (NF-κB) and signal transducers and activators of transcription 3 (STAT3) activation and NF-κB and STAT3-regulated gene expression involved in cell proliferation and invasion. DET and IDET inhibited the activation of NF-κB induced by various inflammatory stimuli such as (tumor necrosis factor (TNF), lipopolysaccharide (LPS), interleukin-1 beta (IL-1β) which activates NF-κB through different pathways. DET and IDET inhibited NF-κB activation at the same step of all these stimuli. Inhibition of NF-κB activation was associated with decreased phosphorylation and the degradation of IκB-α and upstream activation of IκB kinase-alpha/-beta (IKK-α/-β) and IKK kinase activities. DET and IDET down-regulated the expression of NF-κB-regulated gene products involved in invasion such as matrix metalloproteinase (MMP-9) and intercellular adhesion molecule 1 (ICAM-1); cell proliferation such as cyclooxygenase-2 (COX-2), cyclin D1, and cellular-Myc (c-Myc); and anti-apoptosis such as inhibitor of apoptosis protein-1/-2 (IAP-1/-2), B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra-large (Bcl-xL), Bcl-2-related protein A1 also known as Bfl-1/A1, TNF receptor-associated factor (TRAF1), FADD-like IL-1beta-converting enzyme (FLICE)/caspase-8-inhibitory protein (FLIP), and survivin). DET inhibits the activation of STAT3 by reducing phosphorylation at tyrosine-705 and up-regulates the suppressor of cytokine signaling 3 (SOCS3) which is a major component for the negative regulation of the IL-6 signaling cascade; ├ Inhibition, ↑ Up-regulation.