| Summary: | 碩士 === 國立陽明大學 === 藥理學研究所 === 100 === Colorectal cancer (CRC) is one of the most common cancers in the world. In the statistics of 2009 published by Department of Health, Executive Yuan, R.O.C. (Taiwan) showed that colorectal cancer has taken the first place of rate of increase in all kind of cancers. Liver metastasis is frequently found in CRC patients and the prognosis is the worst, and the usual treatments are surgery and/or chemotherapies.
Surgery is the main treatment of CRC. Chemotherapies are used for the adjuvant treatment of inoperable patients with excision of the lesion and reduce the relapse rate. However, some patients have severe side effects such as nausea, vomiting, decreased immune function after received 5-FU-based chemotherapies, and the choice of drugs for chemotherapies still has a few. Hence, finding a new chemotherapeutic drug with fewer side effects is urgently needed.
Adamantane is a kind of compound found in the petroleum. Its related derivatives have been developed in many clinical uses, such as antiviral, neuroprotective, anti-inflammatory, anti-microbial, anti-HIV activities. For anti-cancer activities investigation, the derivativesof adamantine can result in cell apoptosis and growth inhibition to breast cancer, ovarian cancer, and colorectal cancer. Our laboratory have reported the anti-colorectal cancer activity of the rest of compounds: 1,6-Bis[4- (4-amino-3-hydroxyphenoxy)phenyl]diamantine (DPD), N-1- (3,5-dimethyladamantyl)maleimide (DMAMI), and 2,2-Bis(4-(4-amino- 3-hydroxyphenoxy)phenyl)adamantane (DPA). About the previous results of 2,2-Bis(4- (4-amino-3-hydroxyphenoxy)phenyl)adamantine (DPA), it is found to have growth inhibition ability in previous studies. DPA also induces CRC cell cycle arrest in G0/G1 phase, and elevate negative cell cycle regulatory proteins (p21, p27) expression. In addition, it can promote differentiation of CRC cells and increase intercellular adhesion with no acute toxicity in animal model. Furthermore, DPA can be combined with CPT-11 and increase CRT-11 anti-cancer activity.
The aim of this study was to investigate whether DPA could inhibit metastasis of CRC cells. SRB assay results showed that DPA time-dependently inhibited the growth of HCT116 cells. In wound healing assay, the inhibition of HCT116 cells migration was observed. Furthermore, 2 to 4 μM DPA treatment for 48 hours also inhibited the migration HCT116 cells in transwell assay. The animal liver metastasis model showed that tumor generation of SCID mice under 40mg/kg DPA twice a week treatment for 4 weeks is less than mice given only once DPA treatment. Besides, preliminary findings showed that DPA could suppress mTOR expression after 48 hours 4 μM DPA treatment, then decrease downstream metastasis related protein, Twist expression, and finally raise E-cadherin expression.
In conclusion, the potential of inhibition of CRC metastasis through mTOR signaling pathway by DPA can be confirmed.
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