Thus, apoptosis induction by CF was also confirmed by these observations. Nevertheless, to further explain the precise mechanism of CF induced apoptosis in cancer cells, we examined the expression levels of p53, c myc, Bcl 2, pAkt and Akt. We identified p53 as the target of CF. p53 is one of the most important tumour suppressor genes, and it is frequently inactivated in various can cers. p53 modulates various cellular functions, such as apoptosis and cell cycle arrest via transcriptional regu lation. Interestingly, wild type p53 expression was de tected in 47% of colorectal adenocarcinomas, and approximately 70 80% of mesothelioma cells, although having the wild type p53 gene, show a homologous de letion at the INK4A ARF locus containing the p14ARF and the p16INK4A genes, which consequently leads to decreased p53 functions despite the wild type genotype.
MSTO 211 and HCT 116 cell lines endowed wild type p53 and CF treatment increased the expres sion level of p53. Accumulating evidence indicates that c myc has an important function in cell proliferation and apoptosis induction. c Myc expression buy Santacruzamate A is low in quiescent normal cells whereas it is elevated in a broad range of human cancers, such as the malignant pleural mesotheli oma, indicating its key role in tumour development. Human malignant pleural mesothelioma shows elevated c myc expression and it is a transcription factor mediat ing cancer progression, highly overexpressed in 60% of colorectal cancer, indicating that c myc is a hallmark of tumorigenesis.
Studies using conventional c myc transgenic mice, in which the oncogene is constitutively expressed in a given cell type by means of a tissue specific selleck inhibitor promoter, have supported the view that dere gulated c myc, as an initial event, is important for the formation of certain cancers, albeit with a long latency. C myc has also been reported to promote cell cycle re entry and proliferation through repression of p21 and p27 expression. In our experiments, CF in duced an upregulation of p21 and p27 thus, the suppres sion of c myc expression by the nutraceutical may render substantial therapeutic benefits in colorectal can cer and mesothelioma patients by inhibiting the driving activities of c myc in cell proliferation and cell cycle progression. The phosphatidylinositol 3 kinase AKT signal ing pathway plays an important role in survival when cells are exposed to various kinds of apoptotic stimuli.
Recent reports have indicated that the activation of Akt pathway is implicated in conferring resistance to conventional chemotherapy and multiple chemothera peutic agents on cancer cells. Akt is hyperacti vated in a wide range of human tumours as a result of constitutive activation of growth receptors, mutation of PI3K, and inactivation or loss of PTEN phosphatise.