The induction of apoptosis and inhibition of AP-1 activity by TAC-101 (4-[3,5-bis(trimethylsilyl) benzamido] benzoic acid) may result in life prolonging effect in animals bearing metastasizing cancer.
BACKGROUND
The incidence of cancers of the digestive tract has been high among all of the cancers in Japan and the western hemisphere. The poor prognosis of patients, especially those with liver metastases, has become a great challenge for the development of a new drug to cope with this problem.


METHODS
Mice implanted by intrasplenic injection of TMK-1, human gastric carcinoma cells, were used to examine the life-prolonging effect of TAC-101. To elucidate a mechanism of action of TAC-101, the drug-induced apoptosis was assessed by DNA ladder formation whilst the prevention of transcription factor AP-1 binding to its DNA recognition sequence was assessed by gel shift assay.


RESULTS
TAC-101 showed the life prolonging effect in a model of experimental liver metastasis of TMK-1. The antitumor effect, expressed as T/C (%), was 201, 141 and 112%, for TAC-101 (2 mg/kg), ATRA (8 mg/kg) and 5-FU (19 mg/kg), respectively. The in vitro experiments revealed that the anticancer activity of TAC-101 is related to its ability to induce apoptosis within a short period of time in TMK-1 cells and human leukemic cells, HL-60. TAC-101-induced apoptosis was suppressed by the inhibitors of proteases, specifically by Z-Val-Ala-DL-Asp-fluoromethylketone, indicating the involvement of caspase activation. TAC-101 also inhibited, in a concentration-dependent manner, the binding of AP-1 to its DNA binding sites present in the promoter region of the genes involved in the control of cell migration, invasion, and angiogenesis.


CONCLUSIONS
TAC-101 may suppress liver metastasis by the induction of an apoptotic mechanism(s) in cancer cells and possibly by controlling transcriptional activity of AP-1.
Shibata
J
J
Cancer Research Laboratory, Hanno Research Center, Taiho Pharmaceutical Co., Ltd., 1-27 Misugidai, Hanno, Saitama 357-8527, Japan. sibataji@hanno.taiho.co.jp
Murakami
K
K
Aoyagi
Y
Y
Oie
S
S
Hashimoto
A
A
Suzuki
K
K
Sano
M
M
Wierzba
T T
TT
Yamada
Y
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001565:Benzoates / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000517:prevention & control / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*; D014297:Trimethylsilyl Compounds / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001565:Benzoates; C112689:TAC 101; D018808:Transcription Factor AP-1; D014297:Trimethylsilyl Compounds