Effect of the cytostatic butyric acid pro-drug, pivaloyloxymethyl butyrate, on the tumorigenicity of cancer cells.
Previously we have shown that pivaloyloxymethyl butyrate (AN-9), a pro-drug of butyric acid (BA), is a differentiation-inducing agent in a variety of cells. In this report, we demonstrate that AN-9 is a cytostatic but not cytotoxic agent in a myelomonocytic cell line (WEHI); thus, the cells were growth-arrested and differentiated. These late changes in the cells were preceded by changes in the expression of the early regulatory genes, c-myc and c-jun. Although initiation of all these events had already occurred after 1 h exposure to AN-9, the tumorigenicity of these cells tested in Balb/c mice was not affected. A marked reduction in the tumorigenicity of AN-9-treated cells was observed after 4 h of exposure. Exposure of the highly metastatic subclone of Lewis lung carcinoma (3LLD122) to AN-9 resulted in a very pronounced effect on the tumorigenicity of these cells tested in C57BL mice. Unlike WEHI cells, the tumorigenicity of 3LLD122 was almost completely diminished after 1 h of exposure. In both cell types a 10-fold higher concentration of BA did not affect the tumorigenicity of the cells as did AN-9.
Aviram
A
A
Institute of Hematology, Rabin Medical Center, Tel Aviv University, Israel.
Rephaeli
A
A
Shaklai
M
M
Nudelman
A
A
Ben-Dror
I
I
Maron
L
L
Rabizadeh
E
E
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002087:Butyrates / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016758:Genes, jun / Q000187:drug effects; D016259:Genes, myc / Q000187:drug effects; D015479:Leukemia, Myelomonocytic, Acute / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012334:RNA, Neoplasm / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002087:Butyrates; D012334:RNA, Neoplasm; C070441:pivalyloxymethyl butyrate