The In Vitro and In Vivo Antitumor Activity of Vitamin C: K3 Combinations Against Prostate Cancer

Neoplasms of the urinary tract and male genital tract account for 32% of new cancers in males. Prostatic carcinoma is one of the most prevalent malignant tumors of the male reproductive organs, with an estimated 230,110 new cases and 29,900 deaths during the year 2004 in the United States. Although prostate cancer in its early stages is responsive to the standard treatments, no currently available treatment produces a survival advantage to patients with hormone-refractory prostate cancer. This lack of efficacy for the existing protocols points to the need for the development of effective regimens for treating or preventing these tumors. Vitamin C (VC) and vitamin K3 (VK3) administered to androgen independent prostate cancer cell lines in a VC:VK3 ratio of 100:1 exhibit synergistic antitumor activity and preferentially kill tumor cells by autoschizis, a novel type of cell death characterized by exaggerated membrane damage and progressive loss of organelle-free cytoplasm through a series of self-excisions. During this process, the nucleus becomes smaller; cell size decreases to 1/2 - 1/3 of its original size and most organelles surround an intact nucleus in a narrow rim of cytoplasm. While the mitochondria are condensed, tumor cell death does not result from ATP depletion. However, administration of the vitamin combination does: induce a G1/S and a G2/M block in the cell cycle, diminish DNA synthesis, increase hydrogen peroxide (H2O2) production and decrease cellular thiol levels. These effects can be prevented by the addition of catalase to scavenge the H2O2. There is a concurrent 8- to 10-fold increase in intracellular Ca2+ levels. Electrophoretic analysis of DNA reveals degradation due to the caspase-3 independent reactivation of DNase I by VK3 and DNase II by VC. Redox cycling of the vitamins is believed to increase oxidative stress until it surpasses the reducing ability of cellular thiols and induces Ca2+ release which triggers activation of Ca2+ dependent DNase and leads to degradation of DNA. Recent experiments indicate oral VC :VK3 increases the life span of tumor bearing nude mice and significantly reduces the growth rate of solid tumors without any significant toxicity by reactivating DNase I and II. Experimental animal studies indicate that autoschizis is also evident when the vitamin combination is administered to nude mice with implanted human prostate tumors. In a pilot clinical trial, end-stage prostate cancer patients given oral VC:VK3 are monitored by measuring prostate-specific antigen (PSA, a known serum marker of prostate tumor cells specific activity) and total serum homocysteine (a marker of tumor cell numbers with sensitivity for early detection of tumor cell death). The results show that the vitamin combination induces an immediate drop in tumor cell numbers, while serum PSA levels show an initial rise and a subsequent drop to below pretreatment levels. Taken together these facts suggest that the vitamin combination may offer great potential as a new antitumoral chemotherapy. The following chapter discusses the mechanisms of action employed by these vitamins to induce tumor specific death by autoschizis and examines the potential of the vitamin combination as an antitumor agent, chemosensitizer or a radiosensitizer in the treatment of prostatic neoplasms.