The cytotoxic and mechanistic effects of aaptamine on hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is the fifth most common form of cancer and the third most frequent cause of cancer-associated mortality worldwide. We isolated aaptamine from the marine sponge Aaptos, and synthesized derivatives of this compound. Aaptamine and synthetic derivatives displayed various biological activities. This represents the first account of studies on the effects of aaptamine and its derivatives in hepatocarcinogenesis. In this study, Cell Counting Kit (CCK8) was used to evaluate the anti-proliferative effect of aaptamine on HCC in vitro. Additionally, a subcutaneous xenograft model was used to determine if aaptamine could inhibit hepatocellular carcinoma in vivo. We also used RT-PCR and Western blot to analyze the mechanisms behind these effects. Our results showed that aaptamine has anti-proliferation effects on the cell lines LM3 and HepG2. Aaptamine also suppressed the colony-formation ability of HCC cells. We found that aaptamine treatment led to cell cycle arrest in HCC cells, reduced the expression of SOX9 and CDK2. Significant anti-tumor effects were observed in aaptamine-administered tumor-bearing mice as compared to controls. However, structural changes made to aaptamine yielded two derivatives for which all the effects listed above were considerably reduced as compared to the original compound aaptamine. In conclusion, aaptamine is demonstrated for the first time to inhibit liver cancer progression. The aaptamine-induced cell cycle arrest was associated with the increased binding of p21 to Cdk2-cyclin D/E complexes, inhibition of Cdk2 kinase activity in HCC cells. Furthermore, aaptamine appears to be a promising and efficient treatment of liver cancer HCC-LM3 in vivo. We have also uncovered structural changes that might affect the biological activity. The work provides a promising drug candidate for HCC treatment.
Qiao-lu
QL
Li
Ping-ping
PP
Zhang
Pei-qin
PQ
Wang
Hao-bing
HB
Yu
Fan
F
Sun
Wen-zheng
WZ
Hu
Wen-hui
WH
Wu
Xin
X
Zhang
Fei
F
Chen
Zhi-yong
ZY
Chu
Jun-ping
JP
Zhang
Shun-shen
SS
Chen
Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 PuJian Road, Pudong District, Shanghai 200127, China. franklin67@126.com.
Hou-wen
HW
Lin
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D003603:Cytotoxins / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015394:Molecular Structure; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003603:Cytotoxins; D009287:Naphthyridines; C043986:aaptamine