Inhibition of the development of metastases by dietary vitamin C:K3 combination
Introduction
The influence of dietary components on tumor growth and development has recently become a subject of major interest Williams and Dickerson, 1990, Roberfroid, 1991, Milner, 1994. Amongst different alimentary factors, vitamin C and vitamin K3 were investigated as possible antitumor agents Park et al., 1980, Prasad et al., 1981, Gold, 1986. These vitamins were of particular interest because vitamin C (ascorbic acid or sodium ascorbate) was shown to exclusively reactivate acid DNase (DNase II) in malignant tumor cells, while vitamin K3 (2-methyl-1-4-naphthoquinone) selectively reactivated alkaline DNase (DNase) Taper, 1980, Taper et al., 2001.
These observations were of great interest because previously published studies demonstrated that the activity of alkaline and acid DNases was inhibited in non-necrotic cells of malignant tumors in human and experimental animals as well as during early stages of experimental carcinogenesis Taper, 1967, Taper et al., 1971a, Taper et al., 1971b, Fort et al., 1974, Taper and Bannasch, 1976. Furthermore, reactivation of alkaline and acid DNase-induced tumor cell death and tumor regression Taper, 1980, Taper et al., 1981. In fact, the tumor growth-inhibiting and chemotherapy-potentiating effects of vitamin C and K3combinations were evaluated using a variety of human tumor cell lines Noto et al., 1989, De Loecker et al., 1993. These in vitro studies were extended to a battery of human urologic tumor cell lines, including DU145, an androgen-independent prostate carcinoma cell line Gilloteaux et al., 1995, Gilloteaux et al., 1999, Venugopal et al., 1996a, Venugopal et al., 1996b, Jamison et al., 1996, Jamison et al., 1997, Jamison et al., 2001. In these studies, autoschizis, a new type of cell death which differs from necrosis and apoptosis, was described Gilloteaux et al., 1998, Gilloteaux et al., 1999, Gilloteaux et al., 2001a, Gilloteaux et al., 2001b, Jamison et al., 2001.
In vivo administration of the vitamin C and K3 combination to ascites tumor-bearing mice (at a single, intraperitoneal dose of vitamin C = 1g/Kg body weight and vitamin K3 = 0.01 g/Kg) synergistically increased the life span of mice by 45% when compared with sham treated control mice. Individual administration of vitamin C and vitamin K3increased life span by 14% and 1.07%, respectively (Taper et al., 1987). Combined vitamin C and K3 administration also potentiated the chemotherapeutic effects of six different cytotoxic drugs commonly utilized in the classical protocols of human cancer treatment (Taper et al., 1987). The same vitamin C and K3 combination also sensitized a mouse tumor that was resistant to vincristine and potentiated the therapeutic effects of radiotherapy Taper and Roberfroid, 1992, Taper et al., 1996. More recently, vitamin C administration with a benzoquinone was shown to inhibit the metastasis of several colon cancer cell lines that had been implanted into immunocompetent mice (Hidvégi et al., 1998). The structural similarity of vitamin K3 (a naphthoquinone) to the benzoquinone employed in these studies suggested that the vitamin C and K3 combination may decrease tumor metastasis as well as inhibiting the growth of the primary tumor.
Metastases are one of the greatest problems in cancer patients. They appear frequently and are the primary cause of mortality in cancer patients (Fidler, 1999). Different mechanisms are involved in the so-called metastatic cascade, including angiogenesis, cellular adhesion, local proteolysis and tumor cell migration Kohn, 1993, Fidler, 1999. Development of chemotherapeutic agents which target and intervene in one or more processes in the metastatic cascade should lead to a favorable outcome for a large number of cancer patients.
The current study evaluates the ability of orally administered vitamin C and K3 to inhibit the development of metastases of mouse liver tumor (TLT) cells that have been implanted into the thigh of C3H mice.
The TLT cell line is a primary liver tumor of spontaneous origin that was first observed in a 2 month old female Swiss-Webster mouse. The TLT tumor was derived from in vivo passage in mice and characterized by Taper and his colleagues at Sloan Kettering Institute for Cancer Research (Taper et al., 1966). Tumor growth is rapid, invasive and not strain-specific. TLT cells were employed because these tumor cells provide an excellent model for metastasis. Unlike many putative metastatic models in which tumor cells are injected into the tail vein of immunosuppressed rodents and “metastasize” to the lungs, a solid primary tumor is formed in the TLT model. Subsequently, cells from the primary tumor recapitulate all the stages of metastasis.
Section snippets
Animals and diets
Young adult male C3H mice weighing 25–30 g at the beginning of experiments were purchased from IFFA Credo, Domaine des Oncins, France and were fed basal diet for experimental animals AO4, supplied by U.A.R., Villemoison-sur-Orge, France. Vitamin C (sodium ascorbate) and vitamin K3 (2-methyl-1,4-naphthoquinone) were purchased from Sigma, St. Louis, MO, USA. Control mice received water ad libitum. The mice in the experimental group received vitamin C and K3 (15 g/0.15 g) dissolved in 1000 ml of
Results
At early stages after tumor transplantation, vitamin C and K3 treatment produced a distinct inhibition of solid and ascitic TLT tumor growth without producing any distinct difference in morphology of treated and control TLT tumors Taper et al., 1987, Taper and Roberfroid, 1992, Taper et al., 1996. However, the progression of intramuscularly transplanted T.L.T. tumors in C3H mice rapidly became lethal and obliged the sacrifice of all mice 42 days after tumor transplantation. This mortality was
Discussion
The results of the current study demonstrated that oral administration of vitamin C and K3 produced a distinct inhibitory effect on the development of metastases in C3H mice bearing an intramuscularly transplanted mouse liver tumor. Detailed microscopic examination of the main organs as well as the lungs and local lymph nodes (other tissues known to harbor metastases from this tumor) revealed a distinct inhibitory effect of oral vitamin treatment on the development of metastases. As was the
Acknowledgements
The authors thank Dr. J. Cumps for statistical analysis, Mrs. R.M. Dujardin for very competent technical assistance and Mrs. E. Ferdinand for careful typing of the manuscripts.
References (60)
- et al.
Cell death by oxidative stress and ascorbic acid regeneration in human neuroectodermal cell lines
European Journal of Cancer
(1995) - et al.
Redox cycling and sulphydryl arylation; their relative importance in the mechanism of quinone cytoxicity to isolated hepatocytes
Chemico Biological Interactions
(1988) - et al.
Synkavit. Radiosensitizing agent in prostate carcinoma
Urology
(1973) - et al.
Flow cytometric and ultrastructural aspects of the synergistic antitumor activity of vitamin C-vitamin K3 combinations against human prostate carcinoma cells
Tissue and Cell
(1996) - et al.
Evaluation of the in vitro and in vivo antitumor activities of vitamin C and K3 combinations against human prostate cancer
Journal of Nutrition
(2001) - et al.
Cytoskeletal alterations in human platelets exposed to oxidative stress are mediated by oxidative and Ca2+-dependent mechanisms
Archives of Biochemistry and Biophysics
(1989) - et al.
Vitamin K3 (menadione) inhibits the growth of mammalian tumor cells in culture
Life Sciences
(1981) Dietary modulation of experimental neoplastic development: role of fat and fiber content and caloric intake
Mutation Research
(1991)- et al.
Synergistic antitumor activity of vitamin C and K3 on human urologic tumor cell lines
Life Sciences
(1996) - et al.
Synergistic antitumor activity of vitamin C and K3 against human prostate carcinoma cell lines
Cell Biology International
(1996)
Vitamins C and K3 kills cancer cells mainly by autoschizis, a novel form of cell death. Basis for their potential use as coadjuvants in anticancer therapy
European Journal of Medicinal Chemistry
Vitamin K3 induces cell cycle arrest and cell death by inhibiting Cdc25 phosphatase
British Journal of Cancer
Stimulation of interferon production
Antibiotiki
Synergistic killing of Ehrlich ascites carcinoma cells by ascorbate and 3-amino-2,2,4-triazole
Oncology
Vitamin C preferential toxicity for malignant melanoma cells
Nature (London)
Potential therapeutic application of the association of vitamins C and K3 in cancer treatment
Current Medicinal Chemistry
Immunomodulating effects of vitamin K preparations and its potentiation by riboxine in acute cold stress
Eksperimentalnaia i Klinicheskaia Farmakologiia
Chemotherapeutic studies on new transplantable mouse liver tumor (Taper liver tumor)
Cancer Research
The effect of ascorbic acid production on human interferon and the antiviral activity in vitro
Acta Pathologica Microbiologica Scandinavica [B]
Effects of sodium ascorbate (vitamin C) and 2-methyl-1,4-naphthoquinone (vitamin K3) treatment on human tumor cell growth in vitro. II. Synergism with combined chemotherapy action
Anticancer Research
Suppression of angiogenesis, tumorigenicity, and metastasis by human prostate cancer cells engineered to produce interferon-β
Cancer Research
Critical determinants of cancer metastasis: rationale for therapy
Cancer Chemotherapy Pharmacology
Gastric carcinogenesis induced in rats by methylnitrosourea (MNU). Morphology and histochemistry of nucleases
Zeitschrift fur Krebsforschung und Klinische Onkologie
Scanning electronmicroscopy and transmission electron microscopy aspects of synergistic antitumor activity of vitamin C-vitamin K3 combinations against human prostatic carcinoma cell
Scanning Microscopy International
Cancer cell necrosis by autoschizis. Synergism of antitumor activity of vitamin C: vitamin K3 on human bladder carcinoma T24 cells
Scanning
Autoschizis: another cell death for cancer cells facilitated by vitamins C and K3 treatment
Molecular Biology of the Cell 10
Autoschizis: another cell death for cancer cells induced by oxidative stress
Ultrastructural aspects of autoschizis: A new cancer cell death induced by the synergistic action of ascorbate/menadione on human bladder carcinoma cells
Ultrastructal Pathology
In vivo synergy of vitamin K3 and methotrexate in tumor bearing animals
Cancer Treatment Reports
Effect of avemar and avemar + vitamin C on tumor growth and metastasis in experimental animals
Anticancer Research
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