Natural gypenosides: targeting cancer through different molecular pathways

Abstract

The second foremost cause of mortality around the word is cancer. Conventional therapies, such as radiation, surgery, and chemotherapy have limited accessibility owing to secondary resistance. Therefore, convenient, safe, and nonresistant drugs are urgently needed. Plant-derived natural products have attracted considerable interest owing to their high efficacy, low toxicity, and convenience. Gypenosides (Gyp) inhibit invasion, migration, metastasis, and proliferation and induce apoptosis in different cancers, including oral, lung, colorectal, hepatocellular, and leukemic cancers through different molecular pathways. This review summarizes Gyp studies on cancer to serve as a reference for further research and clinical trials.

Keywords: Gyp; cancer; chemotherapy; colorectal; hepatocellular; leukemic; lung; oral; radiation therapy; surgery.

Figure 1

Gyp induces apoptosis, causes cell cycle arrest, and inhibits cell proliferation and DNA repair. (A). Gyp increases Ca+ and ROS generation. ROS inhibits MMP and modulates the mitochondrial proteins directly or through the activation of ERK1/2. Consequently, the rate of cytochrome C and AIF translocation from the mitochondria to the cytoplasm increases, and activated caspase-9, in turn, activates caspase-3,7. However, ROS generation induces endoplasmic reticulum stress by activating oxidation-inducing proteins GADD153, PERK, ATF6, and IRE-α. Consequently, they activate caspase-12, which further activates caspase-3,7. Similarly, caspase-3,7 is activated by activating Fas, Fasl, and caspase-8. Activated caspase-3,7 causes DNA damage in cancer cells, leads to cell apoptosis and (B) activates chk-2, p53, and p21, which inhibit CDK2 and cyclin E. However, Gyp inhibits CDK2 and cyclin E by activating p16, p21, and p27. Then, the cells undergo S and G0G1 phase cell cycle arrest. Furthermore, the activated p16, p21, and p27 inhibit the cyclin D1/3k and CDK4/6, leading to S phase cell cycle arrest. (C) Gyp inhibits cancer cell proliferation through two mechanisms. First, when the cell cycle arrest occurs, cell proliferation is inhibited. Second, Gyp inhibits PI3K, AKT, and p70S6K and cell proliferation. (D). Gyp inhibits DNA-repairing genes including MGMT, DNAPK, ATM/ATR, p53, BRCA1, and 14–3–3σ at mRNA level and inhibits DNA repair. Abbreviations: Gyp, gypenosides; ROS, reactive oxygen species; MMP, mitochondrial membrane potential; ATF6, activating transcription factor-6; BRCA1, breast cancer gene 1; IRE, inositol-requiring enzyme; ATM, ATM, ataxia telangiectasia mutated; ATR, ATR, ATM and Rad-related.

Figure 2

Gyp inhibits migration, invasion, and metastasis. Gyp downregulates SOS, RAS, uPA, and FAK, which in turn downregulates Raf, MEK1/2, and ERK1/2. These proteins directly downregulate MMP-2,7,9. On the other side, they inhibit PI3K, which downregulates Rho-A, as well as Akt, NF-kB, COX-2, which further inhibit MMP-2,7,9 and invasion, migration, and metastasis. Abbreviations: Gyp, gypenosides; MMP, mitochondrial membrane potential.