The Prowess of Andrographolide as a Natural Weapon in the War against Cancer

Abstract

There has been a paradigm shift in our understanding about the multifaceted nature of cancer, and a wealth of information has revealed that single-target drugs are not good enough to provide satisfactory clinical outcomes and therapeutic effects for complex diseases which involve multiple factors. Therefore, there has been a reignition to search for natural products having premium pharmacological activities aim to efficiently target multiple deregulated cellular signaling pathways. Andrographolide, a diterpene lactone from Andrographis paniculata was brought into to the limelight because of its ability to inhibit cancer cell proliferation and induce apoptosis. Here we reviewed andrographolide on cellular pathways regulation including Wnt/β-catenin, mTOR, VEGF-mediated intracellular signaling, as well as TRAIL-mediated apoptosis to inhibit cancer development.

Keywords: TRAIL; andrographolide; anti-cancer drug; oncogenic signaling pathways.

Figure 1

Chemical structure of andrographolide.

Figure 2

(A,B) Regulation of JAK-STAT signaling by Andrographolide. Andrographolide effectively inhibited JAK1, JAK2 and STAT3. (C) Andrographolide inhibited phosphorylation of STAT3 on 705th Tyrosine and 727th Serine.

Figure 3

For activation of mTORC1, PIP3 recruited PDK1 to activate AKT. AKT inhibited the TSC complex, which acted as GTPase-activating protein (GAP) on the GTPase RHEB. GTP-bound RHEB structurally associated and activated mTORC1. Energy stress activated LKB1 and AMPK to suppress mTORC1 via inhibition of RAPTOR and activation of the TSC complex1. Andrographolide inhibited RAPTOR (mTORC1) and RICTOR (mTORC2). mTOR has different domains. RAPTOR and RICTOR bind to HEAT repeats of mTOR. Phosphoinositide-dependent kinase 1 (PDK1), liver kinase B1 (LKB1), AMP-activated kinase (AMPK), regulatory-associated protein of mTOR (RAPTOR).

Figure 4

Schematic diagram of regulation of VEGF/VEGFR-driven pathway by andrographolide. Andrographolide effectively inhibited phosphorylation of VEGFR, AKT and ERK. Andrographolide also promoted internalization of EGFR to inhibit cell surface expression of EGFR and reduce EGF/EGFR-driven downstream signaling.

Figure 5

Diagrammatic representation of regulation of TLR4 signaling. Andrographolide inhibited MYD88 mediated activation of NF-κB. Functionally active NF-κB moves into the nucleus to regulate expression of target genes. However, andrographolide inhibited NF-κB activation and prevented its entry into the nucleus.