Inhibition of human hepatocellular carcinoma by L-proline-m-bis (2-chloroethyl) amino-L-phenylalanyl-L-norvaline ethyl ester hydrochloride (MF13) in vitro and in vivo.
A new anticancer tripeptide, L-proline-m-bis (2-chloroethyl) amino-L-phenylalanyl-L-norvaline ethyl ester hydrochloride (MF13), was investigated for its activity and mechanism in human hepatocellular carcinoma (HCC) cell lines. MF13 showed antiproliferative activities in the panel of 7 human HCC cell lines with IC50 in the range of 0.08-2.32 microM. A significant blockade in the S-phase occurred in tumor cells 12 h after their exposure to MF13. The inactivated Rb (phosphorylated Rb, pRb), which is present in the S-phase, was increased within 6 h of treatment. Bcl-2 expression was without change in hepatocarcinoma cells treated with MF13; however, a significant increase of bax was observed, resulting in a decreased ratio of bcl-2/bax. Increased activity of caspase-9, -8 and -3 was detected in the MF13 treated cells, indicating an activated pathway of apoptosis by MF13. Morphological examination as well as DNA gel electrophoresis demonstrated a nuclear fragmentation and DNA degradation in the form of multiple-unit DNA ladder in MF13 treated tumor cells. MF13 alone at 10 mg/kg (i.p.) inhibited HepG2 tumor in nude mice by more than 94% in volume. Bel-7402 tumor originated from a Chinese patient with HCC exhibited a sensitivity to MF13 similar to HepG2 in vivo. Antitumor effect of MF13 in the nude mice bearing human hepatocarcinoma (Bel-7402 or HepG2) was stronger than mitomycin C as well as its precursor m-sarcolysin (p<0.01), and comparable with cyclophosphamide. We believe MF13 merits consideration for further investigation as an agent against human hepatocellular carcinoma.
Hu
Qiong-Ying
QY
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China.
Li
Jian-Nong
JN
Song
Dan-Qing
DQ
Wang
Yan-Ling
YL
Bekesi
George
G
Weisz
Imre
I
Jiang
Jian-Dong
JD
D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation; D004273:DNA, Neoplasm / Q000378:metabolism; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D009842:Oligopeptides / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D009842:Oligopeptides; C108832:MF 13