Abstract
KIOM-C was recently demonstrated to have anti-metastatic activity in highly malignant cancer cells via suppression of NF-κB-mediated MMP-9 activity. In addition, it was reported to be effective for clearance of the influenza virus by increasing production of anti-viral cytokines, such as TNF-α and IFN-γ, and efficacious in the treatment of pigs suffering from porcine circovirus-associated disease (PCVAD). In this study, we investigated whether KIOM-C induces cancer cell death and elucidated the underlying anti-cancer mechanisms. In addition, we examined whether KIOM-C oral administration suppresses in vivo tumor growth of HT1080 cells in athymic nude mice. We initially found that KIOM-C at concentrations of 500 and 1000 µg/ml caused dose- and time-dependent cell death in cancer cells, but not normal hepatocytes, to approximately 50% of control levels. At the early stage of KIOM-C treatment (12 h), cells were arrested in G1 phase, which was accompanied by up-regulation of p21 and p27, down-regulation of cyclin D1, and subsequent increases in apoptotic and autophagic cells. Following KIOM-C treatment, the extent of caspase-3 activation, PARP cleavage, Beclin-1 expression, and LC3-II conversion was remarkably up-regulated, but p62 expression was down-regulated. Phosphorylation of AMPK, ULK, JNK, c-jun, and p53 was increased significantly in response to KIOM-C treatment. The levels of intracellular ROS and CHOP expression were also increased. In particular, the JNK-specific inhibitor SP600125 blocked KIOM-C-induced ROS generation and CHOP expression almost completely, which consequently almost completely rescued cell death, indicating that JNK activation plays a critical role in KIOM-C-induced cell death. Furthermore, daily oral administration of 85 and 170 mg/kg KIOM-C efficiently suppressed the tumorigenic growth of HT1080 cells, without systemic toxicity. These results collectively suggest that KIOM-C efficiently induces cancer cell death by both autophagy and apoptosis via activation of JNK signaling pathways, and KIOM-C represents a safe and potent herbal therapy for treating malignancies.
Highlights
During tumor development, controlled cell proliferation and cell death are frequently disrupted by mutations in oncogenes or tumor suppressor genes [1]
Cells were treated for 48 h with each herb at the individual concentrations present in 500 and 1000 mg/ml doses of Korea Institute of Oriental Medicine (KIOM)-C, and the cell viability was subsequently determined by MTT assay
Analysis of the cell cycle revealed that KIOM-C treatment for 12 and 24 h increased the proportion of cells in G1 phase to 57.14 and 55.53%, respectively, compared with that in untreated control cells (36.69%)(Figure 2A)
Summary
During tumor development, controlled cell proliferation and cell death are frequently disrupted by mutations in oncogenes or tumor suppressor genes [1] These acquired mutations and consequent alterations in the associated signaling pathways lead to resistance to chemotherapy or radiotherapy. PCD plays a pivotal role in regulating organism development, tissue homeostasis, stress responses, and elimination of damaged cells [4]. Under conditions such as nutrient deprivation, hypoxia, and metabolic, oxidative, and genotoxic stresses, autophagy provides the energy required for cellular protein turnover by elimination of harmful proteins and damaged organelles; these are engulfed by vacuoles known as autophagosomes, which are delivered to the lysosome for degradation. Apoptosis is characterized by externalization of phosphatidylserine (PS), cell shrinkage, nuclear condensation, and DNA fragmentation, which is initiated by biochemical modifications, such as caspase and/or endonuclease activation [11]
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