茄紅素對活體內血管新生的作用以及茄紅素合併順鉑在小鼠異體移植肺癌細胞株(LLC1)模式中對原位癌生長和轉移之研究

Abstract

Overall abstract Cancer metastasis is responsible for the cause of treatment failure and deaths in cancer patients. Tumor proliferation and angiogenesis were played an important role in the complex multistep of metastasis process. To reduce the mortality of cancer patients, the blockage of the cancer metastasis cascade is regarded as a powerful strategy in anticancer therapeutics. Recently, phytochemicals such as genistein and curcumin have been reported to exert anticancer effect and may cooperatively or synergistically enhance the effects of anticancer drugs. Lycopene, a carotenoid rich in tomatoes, is an important research topic of chemotherapy. Several studies demonstrated that the anti-cancer effects of lycopene are related to their effectiveness as induction of gap junction intercellular communication, antimetastasis and antiproliferation. In addition, lycopene has been shown to inhibit migration and tube formation in human umbilical vein endothelial cells and decreases the level of vascular endothelial growth factor (VEGF) in nude mice. However, only limited in vitro and indirect data suggest that lycopene possesses anti-angiogenic activity. In chapter 2, to better understand the effect of lycopene on anti-angiogenic effect, we employed ex vivo and in vivo assays to substantiate the anti-angiogenic action of lycopene. Lycopene treatment inhibited ex vivo angiogenesis, as revealed by both rat aortic ring assay and chicken chorioallantoic membrane assay at 2.5-10 micro M and 1-15 micro g (1.86-27.9 nmol/egg) of lycopene respectively. In addition, we showed that lycopene at 400 micro g/plug (subcutaneously, s.c.) completely inhibited VEGF-induced neovascularization assayed by matrigel plug assay in mice. However, it is unclear whether lycopene may have used as adjuvant in combination chemotherapy regimen. In chapter 3, we employed a xenograft tumor model to examine a combination chemotherapy regimen of lycopene and cisplatin on anti-tumor efficacy and possible mechanisms of such an action. The C57BL/6 mice were (injected (s.c.)) once with Lewis lung carcinoma (LLC1); and after 9 days injection lycopene (2 and 5 mg/kg; peroral (p.o.)) or cisplatin (1 mg/kg; intraperitoneal (i.p.)) were supplemented for an additional 21 days. We found that the combination of 5 mg/kg lycopene with cisplatin significantly enhanced the suppressing effect of cisplatin on tumor growth and lung metastasis in LLC1-bearing mice. Mechanistically, the combination of lycopene and cisplatin was found to decrease the protein expression of cyclin D1and proliferating cellular nuclear antigen in primary tumor tissues, leading to decreased tumor growth. In addition, combination of 5 mg/kg lycopene with cisplatin significantly increased protein expression of tissue inhibitor of metalloproteinase (TIMP)-1, -2 in lung tissues, and decreased the plasma level of metalloproteinase (MMP)- 2, -9, VEGF and significantly increased the plasma level of interleukin-12, resulting lung metastasis suppression. In summary, this thesis research demonstrates that lycopene not only exert its anti-angiogenic effect but also enhance the effectiveness of cisplatin on anti-tumor growth and anti-metastasis. These results suggest that the combination of lycopene and cisplatin could be used as an effective means in chemotherapy.