L-Isoleucine and L-Leucine: Tumor Promoters of Bladder Cancer in Rats

Abstract

A 4-week assay for screening tumor promoters of bladder cancer has been developed in which increased agglutinability of isolated rat bladder cells with concanavalin A is used as an indicator. On the basis of this assay system, L-isoleucine and L-leucine were suspected of being possible tumor promoters. Results of 40- to 60-week carcinogenesis experiments in which N-butyl-N-(4-hydroxybutyl)nitrosamine was used as an initiator demonstrate that L-isoleucine and L-leucine promote bladder cancer in rats. This finding may be relevant to the high incidence of human bladder cancer in Western countries, where the diet is rich in protein.

l-Leucine induces growth arrest and persistent ERK activation in glioma cells

“…Accumulating experimental data suggest that high concentrations of various amino acids can also perturb growth of other cell lines (Lind 2004;Nishio et al 1986;Souba 1993;Wakshlag et al 2006). Furthermore, LAT1 has been shown to regulate mTOR (Ishizuka et al 2008;Nicklin et al 2009), which is a potential mechanism by which amino acid imbalance may lead to LAT1 dysfunction.…”

“…LAT1 exhibits high affinity for several nutritionally essential amino acids including leucine (Leu), isoleucine (Ile), valine (Val), phenylalanine, tryptophan, and methionine. There is increasing evidence that these amino acids may compete for LAT1 in the plasma membrane, and that use of high concentrations of various amino acids may perturb neoplastic cell growth (Lind 2004;Nishio et al 1986;Souba 1993;Wakshlag et al 2006). For example, the effect of arginine on cell growth has been widely examined (Lind 2004), while other amino acids have been used to reduce neoplastic cell growth with mixed results (Nishio et al 1986;Souba 1993;Wakshlag et al 2006).…”

Influence of Strain and Diet on Hepatocarcinogenicity of N-Butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in Rats: Slight Inhibition of Preneoplastic Liver Lesion Development by Uracil

“…While DL-tryptophan promoted bladder carcinogenesis initiated/induced by N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide (FANFT) in rats 18 and has been reported to enhance liver carcinogenesis initiated/induced by DEN 33,34 , inhibiting effects have also been observed with DBN 35 and DEN 36 . L-isoleucine and L-leucine may also enhance urinary bladder carcinogenesis initiated/induced by BBN 17 . However, normal contents of amino acid in diets are not considered to influence liver carcinogenesis, and their levels in the MF and CA-1 diets in the present study were very similar.…”

“…Dietary composition also influences the development of u r i n a r y b l a d d e r t u m o r s i n r a t s 1 5 , 1 6 , a n d d i e t a r y supplementation with amino acids may also enhanced urinary bladder carcinogenesis in rats 17,18 . Sodium L-ascorbate (SA) exerts strong promotion effects on the urinary bladder and is therefore used as a positive control substance in I/P bioassays 3,6 .…”

Ethanol-extracted propolis enhances BBN-initiated urinary bladder carcinogenesis via non-mutagenic mechanisms in rats

“…Tobacco smoking is the predominant cause of urinary bladder cancer, but the effects of other risk factors such as dietary patterns are also important. For example, a Western-style diet rich in protein may contribute to urinary bladder cancer incidence (Nishio et al, 1986). Notably, branched chain amino acids (Lleucine and L-isoleucine) exert a promoting effect on rat urinary bladder carcinogenesis by modulating expression of amino acid transporters and tumorigenesis-associated genes in the rat urinary bladder (Xie et al, 2012a(Xie et al, , 2013.…”