![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Department of Urology, Summa Health Foundation and NEOUCOM, Rootstown, OH 44272;
*
Department of Anatomy, Cell Biology and Cell Pathology, LECOM, Erie, PA 16509; and
Laboratoire de Pharmacologie Toxicologique et Cancerologique, Faculté de Médecine et Pharmacie, Université Catholique de Louvain, 1200 Brussels-Woluwé, Belgium
2To whom correspondence should be addressed. E-mail: jmj{at}neoucom.edu
 |
INTRODUCTION |
|---|
 TOP INTRODUCTION Vitamins C and K-3...The combination of vitamins...In vitro studies with...In vivo antitumor activity...REFERENCES |
|---|
28% of new
cancers in males. Prostatic carcinoma is one of the most prevalent
malignant tumors of the male reproductive organs, with an estimated
179,300 new cases and 37,000 deaths during the year 2000 in the United
States (Greenlee et al. 2000
). Treatment options
for prostate cancer range from watchful waiting to radical prostectomy
and include brachytherapy, external beam irradiation and hormonal
ablation therapy (Foster et al. 1997
). Although prostate
cancer in its early stages is responsive to these standard treatments,
patients with hormone-refractory prostate cancer have an overall
median survival of 9–18 mo, and no currently available treatment
produces a survival advantage (Chen et al. 1998
). The
lack of efficacy of the eliciting protocols points to the need for the
development of effective regimens for treating or preventing these
tumors. |
Vitamins C and K-3 as antitumor agents |
|---|
|
TOPINTRODUCTIONVitamins C and K-3...The combination of vitamins...In vitro studies with...In vivo antitumor activity...REFERENCES |
|---|
). In the form of ascorbate, VC
can be oxidized either by single- or two-electron transfer and can
be converted back to ascorbate by NADH-dependent
semidehydroascorbate reductase or glutathione-dependent
dehydroascorbate reductase (De Laurenzi et al. 1995
).
This cycling process generates intracellular
H2O2 and other reactive
oxygen species (ROS) that deplete cellular thiol levels, initiate
membrane lipid peroxidation and result in tumor cell death.
Vitamin K-3 (menadione, 2-methyl-1,4-naphthoquinone) is a synthetic
derivative of vitamin K-1, which exhibits antitumor activity against
liver, cervix, nasopharynx, colon, lung, stomach, breast, leukemia and
lymphoma cell lines (Nutter et al. 1991
, Wu et al. 1993a
and 1993b
). Vitamin K-3 is reduced intracellularly
via one- or two-electron transfer. The two-electron reduction
of quinone to hydroquinone can form nontoxic conjugates or slowly
autoxidize to reform quinone. After the single-electron reduction
of the quinone to semiquinone, the semiquinone reduces oxygen to the
superoxide radical and regenerates the quinone. As a result, redox
cycling can ensue and produce large amounts of superoxide, which can
dismutate via superoxide dismutase to form
H2O2 and
O2 or take part in metal-catalyzed reactions
to form more toxic species of active oxygen. Therefore, if the
single-electron reduction pathway predominates and the rate of
redox cycling of VK-3 exceeds the capacity of the detoxifying enzymes,
oxidative stress occurs (Stubberfield and Cohen 1989
).
This oxidative stress produces a variety of effects on cells, including
reduction of NADP and ATP pools, depletion of glutathione, induction of
single-stranded DNA breaks and oxidation of sulfhydryl groups in
cytoskeletal proteins (Gant et al. 1988
,
Mirabelli et al. 1989
).
|
The combination of vitamins C and K-3 as an antitumor agent |
|---|
|
TOPINTRODUCTIONVitamins C and K-3...The combination of vitamins...In vitro studies with...In vivo antitumor activity...REFERENCES |
|---|
,
McConkey et al. 1988
, Wu et al. 1993a
).
When VC and VK-3 are combined, their interaction fosters the reduction
of VK-3 via one-electron reduction and increases the rate of redox
cycling of the quinone (Jarabak and Jarabak 1995
,
Pething et al. 1983
). These results suggest that
coadministration of VC can increase the potential toxicity of VK-3. In
fact, when Taper and co-workers (Noto et al. 1989
)
combined VC and VK-3 in a ratio (VC/VK-3) of 100:1, the combination
exhibited tumor-specific antitumor activity against human breast,
oral epidermoid and endometrial tumor cell lines at doses that were
10–50 times lower than when either vitamin was administered alone.
Additional studies using a murine ascites transplantable liver tumor
model showed that the VC-VK-3 combination is an effective
chemosensitizer and radiosensitizer that induces little systemic or
major organ pathology (Taper et al. 1987
and 1996
,
Taper and Roberfroid 1992
). A single
intraperitoneal (i.p.) injection of the VC-VK-3 combination into
immunocompetent mice increased life span by 46%. Furthermore,
administration of the VC-VK-3 combination 3 h before
administration of a variety of chemotherapeutic agents increased life
expectancy up to 143%. Although the mechanism of action of these
vitamins has not been elucidated, their antitumor activity has been
attributed to redox cycling of the vitamins and the possible generation
of peroxides and other ROS followed by membrane lipid alteration, DNase
activation and DNA destruction by the VC-VK-3 combination in the
catalase-deficient cancer cells (Noto et al. 1989
,
Taper et al. 1987
and 1992
). |
In vitro studies with human prostate cancer cell lines |
|---|
|
TOPINTRODUCTIONVitamins C and K-3...The combination of vitamins...In vitro studies with...In vivo antitumor activity...REFERENCES |
|---|
and 1996b
). Electron microscopy revealed vitamin-induced
perturbation of nucleolar, mitochondrial and lysosomal structure,
alteration in stress filaments and other cytoskeletal structures
(Gilloteaux et al. 1995
, Jamison et al. 1996
). Despite the mitochondrial damage, tumor cells did not
die from ATP depletion. However, vitamin treatment decreased DNA
synthesis, slightly increased protein synthesis, induced a
G1 phase block in the cell cycle, triggered the
degradation of DNA and decreased cellular thiol levels (Jamison et al. 1996
, Venugopal et al. 1996a
and 1996b
).
These results suggest that redox cycling of the vitamin combination
increased oxidative stress until it surpassed the reducing ability of
the cellular thiols and cellular or genetic damage ensued. |
In vivo antitumor activity of the vitamin C–vitamin K-3 combination |
|---|
|
TOPINTRODUCTIONVitamins C and K-3...The combination of vitamins...In vitro studies with...In vivo antitumor activity...REFERENCES |
|---|
The results of additional in vivo studies, designed to determine the effect of vitamin administration on the growth of solid tumors in nude mice, demonstrated that administration of clinically attainable doses of oral vitamins given with free access in drinking water could significantly reduce the growth rate of solid tumors in nude mice (P < 0.05). These results suggested that the continuous presence or periodic reintroduction of vitamins into the host to maintain elevated circulating levels of vitamins may be required to obtain the optimum antitumor activity and probably mirrors the lability of the vitamins.
Analysis of sections of tumors taken from mice used in solid-tumor
growth experiments indicate that the vitamin combination induced a
novel type of cell death called autoschizis (Gilloteaux et al. 1998
), with degradation of tumor cell DNA (RNA) induced by
alkaline and acid DNase (and possibly RNase) as one of the principal
effectors of tumor cell death (Taper et al. 2000
).
Furthermore, nude mice receiving the vitamin combination by oral gavage
for 4 wk did not exhibit any significant bone marrow toxicity, changes
in organ weight or pathologic changes of these organs. Because the
vitamin combination is a chemosensitizer (Taper et al. 1987
) and a radiosensitizer (Taper et al. 1996
),
combined VC and VK-3 administration may be considered a new nontoxic
adjuvant cancer therapy that can be easily introduced into the
classical protocols of clinical cancer therapy without any
supplementary risk for patients (Taper et al. 2000
).
|
FOOTNOTES |
|---|
3 Abbreviations used: i.p., intraperitoneal; ROS, reactive oxygen species; VC, vitamin C; VK-3, vitamin K-3.
|
REFERENCES |
|---|
|
TOPINTRODUCTIONVitamins C and K-3...The combination of vitamins...In vitro studies with...In vivo antitumor activity...REFERENCES |
|---|
1.
Chen C.-T., Gan Y., Au J. L.-S., Wientjes M. G. Androgen-dependent and -independent human prostate xenograft tumors as models for drug activity evaluation. Cancer Res 1998;58:2777-2783
2. De Laurenzi V., Melino G., Savini I., Annicchiarico-Petruzzelli M., Finazzi-Agro A., Avigliano L. Cell death by oxidative stress and ascorbic acid regeneration in human neuroectodermal cell lines. Eur. J. Cancer 1995;31:463-466
3.
Foster B. A., Gingrich J. R., Kwon E. D., Madias C., Greenberg N. M. Characterization of prostatic epithelial cell lines derived from transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Cancer Res 1997;57:3325-3330
4. Gant T. W., Rao D. N., Mason R. P., Cohen G. M. Redox cycling and suphydryl arylation; their relative importance in the mechanism of quinone cytotoxicity to isolated hepatocytes. Chem. Biol. Interact. 1988;65:157-173[Medline]
5. Gilloteaux J., Jamison J. M., Arnold D., Ervin E., Docherty J. J., Summers J. L. Cancer cell necrosis by autoschizis: synergism of antitumor activity of vitamin C:vitamin K3 on human bladder carcinoma T24 Cells. Scanning 1998;20:564-576[Medline]
6. Gilloteaux J., Jamison J. M., Venugopal M., Giammar D., Summers J. L. Scanning electron microscopy and transmission electron microscopy aspects of synergistic antitumor activity of vitamin C-vitamin K3 combinations against human prostatic carcinoma cells. Scanning Microsc 1995;9:159-173[Medline]
7. Greenlee R. T., Murray T., Bolden S., Wingo P. A. Cancer statistics, 2000. CA-Cancer J. Clin. 2000;50:7-33[Abstract]
8. Jamison J. M., Gilloteaux J., Venugopal M., Koch J. A., Sowick C., Shah R., Summers J. L. Flow cytometric and ultrastructural aspects of the synergistic antitumor activity of vitamin C-vitamin K3 combinations against human prostatic carcinoma cells. Tissue Cell 1996;28:687-701[Medline]
9. Jarabak R., Jarabak J. Effect of ascorbate on the DT-diaphorase-mediated redox cycling of 2-methyl-1,4-naphthoquinone. Arch. Biochem. Biophys. 1995;318:418-423[Medline]
10. Juan C. C., Wu F.Y.-H. Vitamin K3 inhibits growth of human hepatoma HepG2 cells by decreasing activities of both p34cdc2 kinase and phosphatase. Biochem. Biophys. Res. Commun. 1993;190:907-913[Medline]
11. McConkey D. J., Hartzell P., Nicotera P., Wyllie A. H., Orrenius S. Stimulation of endogenous endonuclease activity in hepatocytes exposed to oxidative stress. Toxicol. Lett. 1988;42:123-130[Medline]
12. Mirabelli F., Salis A., Vairetti M., Bellomo G., Thor H., Orrenius S. Cytoskeletal alterations in human platelets exposed to oxidative stress are mediated by oxidative and Ca2+-dependent mechanisms. Arch. Biochem. Biophys. 1989;270:478-488[Medline]
13. Noto V., Taper H. S., Jiang Y. H., Janssens J., Bonte J., De Loecker W. Effects of sodium ascorbate (vitamin C) and 2-methyl-1,4-naphthoquinone (vitamin K3) treatment on human tumor cell growth in vitro. I. Synergism of combined vitamin C and K3 action. Cancer 1989;63:901-906[Medline]
14. Nutter L. M., Cheng A. L., Hung H. L., Hsieh R. K., Ngo E. O., Liu T. W. Menadione: spectrum of anticancer activity and effects on nucleotide metabolism in human neoplastic cell lines. Biochem. Pharmacol. 1991;41:1283-1292[Medline]
15.
Pething R., Gascoyne P.R.C., Mc Laughlin J. A., Szent-Gyorgi A. Ascorbate-quinone interactions: electrochemical, free radical and cytotoxic properties. Proc. Natl Acad. Sci. U.S.A. 1983;80:129-132
16. Stubberfield C. R., Cohen G. M. Interconversion of NAD(H) to NADP(H). A cellular response to quinone-induced oxidative stress in isolated hepatocytes. Biochem. Pharmacol. 1989;38:2631-2637[Medline]
17. Taper H. S., de Gerlache J., Lans M., Roberfroid M. Non-toxic potentiation of cancer chemotherapy by combined C and K3 vitamin pre-treatment. Int. J. Cancer 1987;40:575-579[Medline]
18. Taper, H. S., Jamison, J. M., Gilloteaux, J., Gwin, C. A., Gordon, T. & Summers, J. L. (2000) In vivo reactivation of DNases in implanted human prostate tumors following administration of a vitamin C:K3 combination. J. Histochem. Cytochem. (in press).
19. Taper H. S., Keyeux A., Roberfroid M. Potentiation of radiotherapy by nontoxic pretreatment with combined vitamins C and K3 in mice bearing solid transplantable tumor. Anticancer Res 1996;16:499-504[Medline]
20. Taper H. S., Roberfroid M. Non-toxic sensitization of cancer chemotherapy by combined vitamin C and K3 pretreatment in a mouse tumor resistant to oncovin. Anticancer Res 1992;12:1651-1654[Medline]
21. Venugopal M., Jamison J. M., Gilloteaux J., Koch J. A., Summers M., Giammar D., Sowick C., Summers J. L. Synergistic antitumor activity of vitamins C and K3 on human urologic tumor cell lines. Life Sci 1996a;59:1389-1400[Medline]
22. Venugopal M., Jamison J. M., Gilloteaux J., Koch J. A., Summers M., Hoke J., Sowick C., Summers J. L. Synergistic antitumor activity of vitamin C and K3 against human prostate carcinoma cell lines. Cell Biol. Int. 1996b;20:787-797[Medline]
23. Wu F.Y.-H., Chang N.-T., Chen W.-J., Juan C.-C. Vitamin K3-induced cell cycle arrest and apoptotic cell death are accompanied by altered expression of c-fos and c-myc in nasopharyngeal carcinoma cells. Oncogene 1993a;8:2237-2244[Medline]
24. Wu F.Y.-H., Liao W.-C., Chang H.-M. Comparison of antitumor activity of vitamins K1, K2 and K3 on human tumor cells by two (MTT and SRB) cell viability assays. Life Sci 1993b;52:1797-1804[Medline]
This article has been cited by other articles:
|
|
 |
|
  R. Beck, J. Verrax, N. Dejeans, H. Taper, and P. B. Calderon Menadione Reduction by Pharmacological Doses of Ascorbate Induces an Oxidative Stress That Kills Breast Cancer Cells International Journal of Toxicology, January 1, 2009; 28(1): 33 - 42. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Nimptsch, S. Rohrmann, and J. Linseisen Dietary intake of vitamin K and risk of prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg) Am. J. Clinical Nutrition, April 1, 2008; 87(4): 985 - 992. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Rooseboom, J. N. M. Commandeur, and N. P. E. Vermeulen Enzyme-Catalyzed Activation of Anticancer Prodrugs Pharmacol. Rev., March 1, 2004; 56(1): 53 - 102. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
