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|a Cancer is one of the major public health problems in the world. Pancreatic cancer is the 8th most common cause of cancer death worldwide because of its poor prognosis. New Zealand is the fourth highest cancer incidence country worldwide, and pancreatic cancer is the leading cause of cancer mortality after diagnosis in New Zealand. Gemcitabine a novel deoxycytidine analogue, first conceptualized and synthesized in 1980s, is used as the first line chemotherapeutic agent for the treatment of pancreatic cancer at present. However, gemcitabine alone is not satisfactory in the clinical treatment of pancreatic cancer: chemo-resistance is still found in the treatment process. Even combined with other chemo or radio-therapeutic agents it still shows limited efficacy, with severe side effects. According to cytotoxicity (MTT assay) analysis, gemcitabine showed its inhibition effect to human pancreatic cancer cell lines MIA PaCa-2, PANC-1 and human embryonic kidney cell line HEK 293 in a dose-dependent manner. Different cell lines response to gemcitabine with different sensibilities. The gemcitabine IC50 value after 72 hours exposure for MIA PaCa-2 cells was 16.00 ± 0.47 nM, PANC-1 cells was 48.55 ± 2.30 μM and for HEK 293 cells was 48.82 ± 3.27 nM. The anti-cancer activity of gemcitabine is primarily performed by impairing DNA synthesis. Gemcitabine showed cytostatic and cytotoxic effects to pancreatic cancer cells by blocking cell cycle in G0-G1 or S phase and further induced apoptosis. Fucoxanthin is the most abundant natural carotenoid found in various marine algae, which is thought as a potential natural substance to be developed as a pharmaceutical anticancer agent. Fucoxanthin inhibited human pancreatic cancer cell lines MIA PaCa-2 and PANC-1 in a time- and dose- dependent manner. It also showed a selective inhibition effect towards human embryonic kidney cell line HEK 293. Fucoxanthin showed an anti-proliferative effect when treating human pancreatic cancer cell lines (MIA PaCa-2 and PANC-1) due to its cytostatic and cytotoxic properties. This was accomplished by inducing cell cycle arrest at the G0-G1 phase and/or apoptosis. The fucoxanthin IC50 detected at 72 hours for MIA PaCa-2 was 8.74 ± 0.28 μM, for PANC-1 was 10.58 ± 0.56 μM and for HEK 293 was 8.28 ± 0.30 μM. Fucoxanthin significantly improved the inhibitory effect of gemcitabine to pancreatic cancer cells even at a low concentration range (150,250 and 300 nM). Low doses of fucoxanthin even help enhance the cell viability of HEK 293 cells. The interaction of fucoxanthin and gemcitabine on inhibition of PANC-1 cells was significant (P< 0.01). Fucoxanthin (150, 250, 300 nM) simultaneously combined with gemcitabine (25 and 50 nM) showed significant anti-proliferation effect to MIA PaCa-2 cells in a concentration dependent manner (P< 0.05) in each gemcitabine group (GEM 25 nM group and GEM 50 nM group), compared to gemcitabine treatment alone. Fucoxanthin 10 μM combined with 500 nM gemcitabine, significantly decreased about 7% of PANC-1 cell viability compared to fucoxanthin 10 μM treatment alone (P< 0.05). In the fucoxanthin 20 μM group, the joint inhibitory effect of both gemcitabine 50 nM (P< 0.05) and 500 nM (P< 0.01) was significantly higher than 20 μM of fucoxanthin treating PANC-1 cells alone. Cell cycle results were consistent with the MTT assay results. In summary, the in vitro study of gemcitabine and fucoxanthin on human pancreatic cancer cells showed additive inhibitory effects instead of synergistic effects when combining the two drugs to treat the cells for the designated time course. The findings also demonstrated that fucoxanthin effectively improved the cytotoxicity of gemcitabine even at low concentrations. This study is a beginning phase of research which investigates the anti-proliferative effect of fucoxanthin on pancreatic cancer. Fucoxanthin is considered as a potential candidate for the development of anti-cancer drugs for the treatment of pancreatic cancer as well as for further clinical applications.
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