Abstract
In the present study, we examined the anticancer properties of berberine in KB oral cancer cells with a specific focus on its cellular mechanism. Berberine did not affect the cell viability of the primary human normal oral keratinocytes that were used as a control. However, the viability of KB cells was found to decrease significantly in the presence of berberine in a dose-dependent manner. Furthermore, in KB cells, berberine induced the fragmentation of genomic DNA, changes in cell morphology, and nuclear condensation. In addition, caspase-3 and -7 activation, and an increase in apoptosis were observed. Berberine was also found to upregulate significantly the expression of the death receptor ligand, FasL. In turn, this upregulation triggered the activation of pro-apoptotic factors such as caspase-8, -9 and -3 and poly(ADP-ribose) polymerase (PARP). Furthermore, pro-apoptotic factors such as Bax, Bad and Apaf-1 were also significantly upregulated by berberine. Anti-apoptotic factors such as Bcl-2 and Bcl-xL were downregulated. Z-VAD-FMK, a cell-permeable pan-caspase inhibitor, suppressed the activation of caspase-3 and PARP. These results clearly indicate that berberine-induced cell death of KB oral cancer cells was mediated by both extrinsic death receptor-dependent and intrinsic mitochondrial-dependent apoptotic signaling pathways. In addition, berberine-induced upregulation of FasL was shown to be mediated by the p38 MAPK signaling pathway. We also found that berberine-induced migration suppression was mediated by downregulation of MMP-2 and MMP-9 through phosphorylation of p38 MAPK. In summary, berberine has the potential to be used as a chemotherapeutic agent, with limited side-effects, for the management of oral cancer.
Highlights
Oral cancer consists of malignant lesions in the oral cavity and is one of the most common types of cancer worldwide [1,2]
Dead cells were stained red by ethidium bromide homodimer 1 and were observed to be a significant presence in the KB oral cancer cells that had been treated with 1 μg/ ml berberine
In order to determine whether or not berberine-induced KB oral cancer cell death is related to apoptosis, we measured the extent of representative apoptotic phenomena such as DNA fragmentation, the formation of apoptotic bodies and DNA condensation
Summary
Oral cancer consists of malignant lesions in the oral cavity and is one of the most common types of cancer worldwide [1,2]. Oral cancer occurs predominantly in individuals aged 50 years and above, there has been a 5-6% increase per year in the number of patients under the age of 45 [3,4]. The pathological etiologies of oral cancer are closely associated with mutations in the genes that regulate cell growth, proliferation and apoptosis induced by chronic exposure to carcinogens such as tobacco, alcohol and betel quid [5]. Despite improvements and innovations in both diagnostic techniques and therapeutics, surgery often results in loss of function and disfigurement. Radiotherapy and the overall survival rate of patients with oral cancer have not improved [6]. There is an urgent need for the development of clinically relevant, highly effective chemotherapeutic agents with minimal side-effects
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