Role of Thiol Agents in Protecting Against the Toxicity of Helenalin in Tumor Bearing Mice

Abstract

Helanalin, a sesquiterpene lactone antineoplastic agent, is toxic at therapeutic doses in murine tumors. The toxicity has been assumed to be correlated with the binding of the drug to cellular thiol groups. Studies were undertaken to increase the intracellular level of GSH in the liver, kidney and other tissues to eliminate the toxicity of helenalin in vivo. Combination of helenalin 8 mg/kg/day i.p.) with L-cysteine (100 mg/kg/day), beta-mercaptoethanolamine (20 mg/kg/day), 18-beta-glycyrrhetinic acid (15 mg/kg/day), or 4,4'-diaminodiphenylsulfone (10 mg/kg/day) afforded improvement in survival of mice bearing P-388 lymphocytic leukemia. However, other thiol-elevating agents, anti-oxidants, intracellular buffering agents, and cardiac treatment drugs were not effective. Hydrocortisone, Cortef, treatment with helenalin afforded improvement in life expectancy. Reduced glutathione (GSH) and non-protein sulfhydryl (NPS) levels were not reduced in the liver, kidney, or circulating red blood cells (rbc) by helenalin treatment. After three days treatment of mice with helenalin, GSH levels were reduced and NPS levels elevated in P-388 tumor cells. Administration of L-cysteine, beta-mercaptoethanolamine, 4,4'-diaminodiphenylsulfone, or 18-beta-glycyrrhetinic acid alone caused no alteration in liver GSH but elevated NPS levels; P388 cell GSH and NPS levels were lowered. Combination of any of these agents, after three days, with helenalin afforded increases in P-388 cell GSH and NPS levels. This data would suggest that helenalin toxicity is not related to the lowering of GSH or NPS levels in critical tissues of mice.

Naturally occurring asteriscunolide A induces apoptosis and activation of mitogen‐activated protein kinase pathway in human tumor cell lines

“…In lymphocytes a glutathione depletion has been shown to cause a decreased proliferative activity in these cells 44, 45 because lymphocytes require glutathione for progression from G 1 into S phase 46, 47. This hypothesized effect by AS is supported by previous studies which show that sesquiterpene lactones influence intracellular glutathione levels 48–50. In addition, studies on the cytotoxicity of helenanolides against cancer cell lines differing in their intracellular glutathione levels show a tendency for lower cytotoxicity against cells with a higher glutathione level for helenalin and chamissonolide derivatives 51.…”

Effect of Several Sesquiterpene Lactones on Lipid Peroxidation and Glutathione Level

“…Inhibition of glutathione reductase, an enzyme responsible for glutathione regeneration, enhanced the toxicity of helenalin in hepatocyte cultures. In another experiment three-day treatment with helenalin at 8 mg/kg/ day in tumor bearing BDF 1 mice demonstrated no decrease in GSH level in the kidney and liver (10). We showed that the GSH depletion is a response to a low dose of helenalin 2 2.5mg/kg.…”

“…Helenalin is a constituent of the medicinally used flower heads of Arnica species (3). Its acute toxicity, cytotoxicity (4,5), antiulcer activity (6,7) and effect on many biochemical parameters including protein synthesis, some enzymes activity (8,9) and liver glutathione level (10,11) have been investigated. There are only single reports concerning biological activity of the rest of the above mentioned lactones (1,6).…”

The ambrosanolide cumanin inhibits macrophage nitric oxide synthesis: some structural considerations

“…However, because of its high cytotoxicity, its therapeutic use is limited (Kim, 1980;Hall et al, 1989). It has been proposed that the pharmacological activity as well as the cytotoxicity of helenalin is due to the double alkylation of thiols in the target cells (Hall et al, 1979(Hall et al, , 1980Rüngeler et al, 1999).…”