Abstract
To evaluate the anticancer effect of alpha-tomatine (i.p.) either alone or in combination with doxorubicin (i.v.) in a mouse tumour model. We studied the effect of repeated alpha-tomatine (0.1 - 9 mg/kg) and/or doxorubicin (2 mg/kg) on the growth and mitotic activity of the solid Ehrlich tumour in vivo, as well as on the survival of the tumour-bearing mice. Monotherapy with alpha-tomatine had a significant dose-dependent anticancer effect which peaked at 1mg/kg. This was shown by both slowed tumour growth and reduced tumour cell proliferation. We also provide the first evidence that the combination alpha-tomatine (1 mg/kg) and doxorubicin (2 mg/kg) had a synergistic effect and significantly prolonged the survival of the mice. Neither alpha-tomatine nor doxorubicin influenced the infiltration of tumours with CD3+ lymphocytes; nor were we able to find an in vivo modulation of the key molecules of two regulatory pathways reported in vitro as the principal anti-cancer mechanisms of alpha-tomatine, i.e. iNOS and phosphorylated ERK2. However, alpha-tomatine still led to intracellular DNA inhibition and protein synthesis in Ehrlich tumour cells in a short-term culture ex vivo with IC50 values of 8.7 and 6.6 µM. The results suggest that ΤΟΜ, especially in combination with doxorubicin, may be a promising agent for the treatment of malignant solid tumours. Despite growing knowledge of the mechanisms of ΤΟΜ action in cancer cells, most aspects remain unclear. Parallel organ toxicity, especially potential liver effects, requires careful attention when performing in vivo studies in the future.
Highlights
We evaluated in detail the effect of the repeated intraperitoneal administration of ΤΟΜ at doses from 0.1 to 9 mg/kg, either alone or in combination with doxorubicin, on tumour growth, mitotic activity, and the survival of immunocompetent mice bearing the solid Ehrlich tumour
Only the combination of 1 mg/kg of ΤΟΜ with DOX prolonged the survival time significantly compared with untreated tumour-bearing control mice (P
Western blot To assess the major pathways that may be involved in anticancer process, we evaluated the presence of the CD3 antigen – the indicator of T-lymphocytes; phosphorylated ERK2 – a key active regulatory molecule; and iNOS – a target downstream of NF-κB as an indicator of its activation
Summary
Α−Tomatine (TOM) is the major glycoalkaloid of tomato (Solanum lycopersicum L., syn.: Lycopersicon esculentum Mill.). Shih et al.[10] found ΤΟΜ (c ≤ 2 μmol/L) to suppress invasion and migration in a human lung adenocarcinoma cell line It inhibited the phosphorylation of Akt (protein kinase B), a serine-threonine kinase which regulates the function of many cellular proteins involved in metastasis and the proliferation of cancer cells[11], and the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK 1,2). Despite the very encouraging data from in vitro experiments, to our knowledge only one other very recently published study has investigated the anticancer effect of ΤΟΜ in a mammal model in vivo It found that TOM at a dose of 5 mg/kg (administered i.p. every other day) inhibits the growth of HL-60 leukaemia xenografts in immunodeficient mice[16]. As a surrogate for potential toxicity, serum bilirubin and liver enzymes were measured
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