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It has been reported that vitamin C plays an effective role in the treatment and prevention of cancer, but its specific mechanism is still not fully understood. In particular, the effect of vitamin C on the treatment and prevention of colorectal cancer, which has been increasingly a common disease in South Korea due to westernized diet of many Koreans, is still largely unknown. Therefore, we have examined the effects of vitamin C on the induction of apoptosis on HCT-8, human colon cancer cell line. We have first confirmed that the optimal concentrations of vitamin C for the induction of apoptosis on human colon cancer cell line, HCT-8 is 2 mM of vitamin C. Here we demonstrated that vitamin C induced ER stress through redox imbalance as antioxidant and, increased cytosol calcium level. Then, we investigated the changes of ER-stress induced molecules. As a result, the phosphorylation of pro-apoptotic protein, Bad decreased and Bad, which was subsequently released from 14-3-3, was translocated to the mitochondria. In addition, we also found that the vitamin C increased expression of pro-apoptotic protein, Bax and tumor suppressor gene product, p53, which usually resulted in apoptosis, in a time dependent manner. Moreover, we have witnessed that vitamin C treatment disrupts mitochondrial membrane potential in HCT-8, human colon cancer cell line. Taken together, vitamin C induced redox imbalance, resulting in apoptosis in human colon cancer cells by both endoplasmic reticulum stress and Bad/p53/Bax-mediated activation of mitochondrial pathway.

Overexpression of cyclooxygenase-2 (COX-2) frequently occurs in several malignancies and the type I insulin-like growth factor receptor (IGF-IR) is important for growth, transformation, proliferation and protection from apoptosis. However the interaction between COX-2 expression and IGF-I axis in human melanoma remains obscure. Although inhibition of COX-2 could reduce tumor volumes in various murine models, selective COX-2 inhibitors could increase cardiovascular risk. Therefore, we studied the effects of vitamin C, which is known as the potent inhibitor of proliferation of human melanoma cell line, SK-MEL-2. We confirmed that the optimal concentration of vitamin C for the inhibition of proliferation without inducing apoptosis is 1.0 mM. ELISA for IGF-I and IGF-II conducted after treatment with NS-398 and vitamin C revealed that the production of IGF-II was decreased by COX-2 inhibition. RT-PCR for IGF-IR after COX-2 inhibition using NS-398 or COX-2 siRNA showed the inhibition of COX-2 expression led to dramatic down-regulation of IGF-IR expression which is restored by adding exogenous PGE2, which is produced by the enzymatic action of COX-2. Next we observed that both COX-2 and IGF-IR expression were significantly decreased after treatment of 1.0 mM vitamin C. Interestingly exogenously treated IGF-II induced IGF-IR expression and exogenous PGE2 treatment restored IGF-IR expression which is down-regulated by vitamin C. These findings suggest that vitamin C could modulate IGF-II production and then down-regulate the expression of IGF-IR by the inhibition of COX-2 expression, followed by suppression of the proliferation of human melanoma cell line, SK-MEL-2.

CD40 has been shown to play a critical role in normal B-cell development and function. Interestingly, CD40 has also demonstrated to be expressed at high levels on some human cancers, including the breast cancer. However, the function of CD40 expressed on tumor cells is still not fully understood. In this study, therefore, the function of CD40 on tumor cells in the aspect of the production of Transforming Growth Factor-beta (TGF-β) was investigated after CD40 stimulation. First, high expression of CD40 on the human breast cancer cell line, MDA-MB231 was observed. The tumor cells were incubated for 24 hr in the presence of agonistic anti-CD40 antibodies or sCD40 ligands, the productions of TGF-β were dramatically increased in each cases. Human T cells purified from peripheral blood were stimulated with PHA and ionomycin. And then cells were cultured with MDA-MB231 for 24 hr. As a result, significantly increased production of TGF-β was observed. Taken together, TGF-β production by breast cancer cells increased via the ligation of CD40 on their surface with CD40L on the surface of T cells. Thus, considering that TGF-β serves dual roles not only in promoting tumor progression and metastasis, but also in immune suppression, these results give an important clue for understanding the mechanism of the immune suppression by tumor cells.

Malignancies of lung are the leading causes of cancer mortality in world wide and there are so many limitations in early detection of lung cancer, which eventually made the cancer detected at advanced stage. Conventional cytotoxic drugs have showed more increased response rate with grave toxicities. Recently, successful therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor in lung cancer patients have been reported, although a mono-therapy still showed low response rate. Here, we investigated to elucidate whether the vitamin C has the adjuvant role as an antioxidant or other functions in EGFR tyrosine kinase inhibitor, gefitinib (Iressa ¢â), therapy in lung cancers. We used three kinds of human non-small cell lung cancer cell (NSCLC) lines depending on EGFR mutation, A549, Calu-3 and HCC827. A549 and Calu-3 are NSCLC cell lines which have wild type EGFR domain and showed relative resistance to gefitinib treatment. HCC827 is well known cell line of EGFR domain mutation. Vitamin C showed reduction of S phase in cell cycle and had function as an anti-oxidant. Also that could induce synergistic effects of EGFR tyrosine kinase inhibitor therapy in cellular proliferation and down-regulation of EGFR phosphorylation, AKT & ERK activation. Synergistic inhibitory effects of vitamin C with EGFR tyrosine kinase inhibitor therapy are showed in both wild and mutant EGFR cell lines. In this present study, we demonstrated an possible adjuvant role of vitamin C in EGFR tyrosine kinase inhibitor therapy in human NSCLC.