Killing cancer with platycodin D through multiple mechanisms

Abstract

Cancer is a multi-faceted disease comprised of a combination of genetic, epigenetic, metabolic and signalling aberrations which severely disrupt the normal homoeostasis of cell growth and death. Rational developments of highly selective drugs which specifically block only one of the signalling pathways have been associated with limited therapeutic success. Multi-targeted prevention of cancer has emerged as a new paradigm for effective anti-cancer treatment. Platycodin D, a triterpenoid saponin, is one the major active components of the roots of Platycodon grandiflorum and possesses multiple biological and pharmacological properties including, anti-nociceptive, anti-atherosclerosis, antiviral, anti-inflammatory, anti-obesity, immunoregulatory, hepatoprotective and anti-tumour activities. Recently, the anti-cancer activity of platycodin D has been extensively studied. The purpose of this review was to give our perspectives on the current status of platycodin D and discuss its anti-cancer activity and molecular mechanisms which may help the further design and conduct of pre-clinical and clinical trials to develop it successfully into a potential lead drug for oncological therapy. Platycodin D has been shown to fight cancer by inducing apoptosis, cell cycle arrest, and autophagy and inhibiting angiogenesis, invasion and metastasis by targeting multiple signalling pathways which are frequently deregulated in cancers suggesting that this multi-target activity rather than a single effect may play an important role in developing platycodin D into potential anti-cancer drug.

Keywords: apoptosis; autophagy; invasion; metastasis; platycodin D; saponin.

Figure 1

(A) Chemical structure and natural source of platycodin D. (B), Platycodin D inhibits cancer progression and development by inhibiting proliferation, survival, angiogenesis, invasion, metastasis and cell cycle progression, and ultimately inducing apoptosis and autophagy by modulating expressions of various genes.

Figure 2

A schematic model of platycodin D‐induced apoptosis in cancer cells. Platycodin D induces ROS generation and increases the expression of transcriptional factor FOXO3a. ROS activates ASK‐1 by reducing the expression of thioredoxin. Once activated, ASK‐1 activates p38 and JNK by phosphorylation. Transcriptional factor FOXO3a and activated p38 and JNK triggered both extrinsic and extrinsic apoptosis by inducing the transcription of apoptosis related genes such as FasL, Bim, c‐Jun. Moreover, platycodin D induces intrinsic apoptosis by modulating the expression of Bcl‐2 family proteins and mitochondrial dysfunction, inducing endoplasmic reticulum stress, increasing the expressions of Egr‐1 and NAG‐1 which results in caspase‐3 activation. Caspase‐3 then executes apoptotic cell death by cleaving PARP and activating CAD.

Figure 3

A schematic representation of platycodin D‐induced G2/M phase cell cycle arrest in cancer cells. Platycodin D inhibits G2‐M phase transition by increasing the expression of transcription factor FOXO3a, p53, p21 and Weel, and decreasing the expression of MDM2 and induces M phase arrest by sustainable tubulin polymerization. Binding of ligand such as growth factor (EGF) to the growth factor receptor (EGFR) promotes the activation of downstream pro‐survival signalling pathways such as PI3K/AKT and MAPK/ERK pathways. Activated AKT and ERK translocate to the nucleus and inhibit the transcription of apoptosis promoting (Bim, FasL, TRAIL) and cell cycle regulatory genes (p21, p27) by phosphorylating FOXO3a and exporting it out of nucleus. ERK regulates the expression of MDM2 that ubiquitinates FOXO3a in response to ERK pathway activation leading to proteasomal degradation. Platycodin D induces G2/M phase arrest and apoptosis by increasing the expression of FOXO3a in nucleus by inhibiting AKT and ERK.

Figure 4

Molecular mechanism of platycodin D‐induced autophagy in cancer cells: Platycodin D induces autophagy through PI3K/AKT and MAPK pathways. Platycodin D converted LC3‐I to LC3‐II by increasing the expression of Beclin‐1, Atg3 and Atg 7. Inhibition of PI3K/AKT and activation of MAPK signalling pathways by platycodin D resulted in autophagy by accumulating LC3‐II in cancer cells ($⊢$Inhibition; ⟵ Activation).