Targeting Apoptosis and Multiple Signaling Pathways with Icariside II in Cancer Cells

Abstract

Cancer is the second leading cause of deaths worldwide. Despite concerted efforts to improve the current therapies, the prognosis of cancer remains dismal. Highly selective or specific blocking of only one of the signaling pathways has been associated with limited or sporadic responses. Using targeted agents to inhibit multiple signaling pathways has emerged as a new paradigm for anticancer treatment. Icariside II, a flavonol glycoside, is one of the major components of Traditional Chinese Medicine Herba epimedii and possesses multiple biological and pharmacological properties including anti-inflammatory, anti-osteoporosis, anti-oxidant, anti-aging, and anticancer activities. Recently, the anticancer activity of Icariside II has been extensively investigated. Here, in this review, our aim is to give our perspective on the current status of Icariside II, and discuss its natural sources, anticancer activity, molecular targets and the mechanisms of action with specific emphasis on apoptosis pathways which may help the further design and conduct of preclinical and clinical trials. Icariside II has been found to induce apoptosis in various human cancer cell lines of different origin by targeting multiple signaling pathways including STAT3, PI3K/AKT, MAPK/ERK, COX-2/PGE2 and β-Catenin which are frequently deregulated in cancers, suggesting that this collective activity rather than just a single effect may play an important role in developing Icariside II into a potential lead compound for anticancer therapy. This review suggests that Icariside II provides a novel opportunity for treatment of cancers, but additional investigations and clinical trials are still required to fully understand the mechanism of therapeutic effects to further validate it in anti-tumor therapy.

Keywords: Apoptosis; Cancer; Herba epimedii; Icariside II; Multiple signaling pathways.

Figure 1

Chemical structure and natural sources of Icariside II. Icariside II is a major metabolite of Icariin. Substitution or removal of various groups at positions 1, 2, and 3 results in different flavonol compounds as described in Natural Sources section. Icariside II is major component of Herba epimedii and Cortex periplocae. Herba epimedii (A+B+C+D+E) is made up of dried aerial parts of Epimedium species such as E.brevicornum (A), E. pubescens Maxim (B), E. koreanum Nakai (C), E. sagittatum Maxim (D), and E.devidii (E). Cortex periplocae (F) is made up of dry roots of Chinese herb Periploca sepium Bunge (F).

Figure 2

Icariside II inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple molecular targets.

Figure 3

Interaction of Icariside II with apoptosis signaling pathways: Binding of Ligand such as growth factor (EGF) to the growth factor receptor (EGFR) promotes the activation of downstream pro-survival signaling pathways. These include the SRC and Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3), PI3K/AKT, and RAS/RAF/MEK/ERK pathways. Activation of these pathways promotes survival, proliferation, invasion and metastasis. Icariside II inhibits all these three pathways at multiple levels. Activated AKT activates NF-КB and mTOR while inactivate GSK-3β via phosphorylation. Suppression of GSK-3β leads to stabilization of β-catenin which induces the expression of downstream target genes such as cyclin D1 and survivin and thus promotes survival and tumorigenesis. ( Activation; Inhibition; Activation by Icariside II; Inhibition by Icariside II )