Vitamins C and K3 Sensitize Human Urothelial Tumors to Gemcitabine

Kassouf, Wassim; Highshaw, Ralph A.; Nelkin, Gina M.; Dinney, Colin P.; Kamat, Ashish M.

doi:10.1016/j.juro.2006.06.042

Cited by 37 publications

(22 citation statements)

References 18 publications

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“…11 Our results demonstrate that oral Apatone significantly increased the PSADT of almost all the patients without concomitantly decreasing PSA, while co-administration of Apatone with known chemotherapeutic agents in other cancers resulted in a synergistic increase in antitumor activity. 8,20 These results suggest that Apatone may find use in the clinic as a co-adjuvant therapy potentially in addition to docetaxol. Our decision not to include patients with alkaline phosphatase over 200 U/l may have excluded a number of men with osteoblastic bone lesions from metastases.…”

Section: Discussionmentioning

confidence: 96%

A 12 Week, Open Label, Phase I/IIa Study Using Apatone^® for the Treatment of Prostate Cancer Patients Who Have Failed Standard Therapy

Tareen

Summers²,

Jamison³

et al. 2008

Int. J. Med. Sci.

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Purpose:To evaluate the safety and efficacy of oral Apatone ® (Vitamin C and Vitamin K 3 ) administration in the treatment of prostate cancer in patients who failed standard therapy. Materials and Methods: Seventeen patients with 2 successive rises in PSA after failure of standard local therapy were treated with (5,000 mg of VC and 50 mg of VK 3 each day) for a period of 12 weeks. Prostate Specific Antigen (PSA) levels, PSA velocity (PSAV) and PSA doubling times (PSADT) were calculated before and during treatment at 6 week intervals. Following the initial 12 week trial, 15 of 17 patients opted to continue treatment for an additional period ranging from 6 to 24 months. PSA values were followed for these patients. Results: At the conclusion of the 12 week treatment period, PSAV decreased and PSADT increased in 13 of 17 patients (p ≤ 0.05). There were no dose-limiting adverse effects. Of the 15 patients who continued on Apatone after 12 weeks, only 1 death occurred after 14 months of treatment. Conclusion: Apatone showed promise in delaying biochemical progression in this group of end stage prostate cancer patients.

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Section: Discussionmentioning

confidence: 96%

A 12 Week, Open Label, Phase I/IIa Study Using Apatone^® for the Treatment of Prostate Cancer Patients Who Have Failed Standard Therapy

Tareen

Summers²,

Jamison³

et al. 2008

Int. J. Med. Sci.

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“…This approach was beneficial when the drug combination was co-administrated with known chemotherapeutic agents [26]. Accordingly, co-administration of sub-lethal doses of AA+VK3 (redox-active system) with the redox-silent α-TOS resulted in efficient in vitro cell death.…”

Section: Discussionmentioning

confidence: 99%

Alpha-Tocopheryl Succinate Inhibits Autophagic Survival of Prostate Cancer Cells Induced by Vitamin K3 and Ascorbate to Trigger Cell Death

et al. 2012

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BackgroundThe redox-silent vitamin E analog α-tocopheryl succinate (α-TOS) was found to synergistically cooperate with vitamin K3 (VK3) plus ascorbic acid (AA) in the induction of cancer cell-selective apoptosis via a caspase-independent pathway. Here we investigated the molecular mechanism(s) underlying cell death induced in prostate cancer cells by α-TOS, VK3 and AA, and the potential use of targeted drug combination in the treatment of prostate cancer.Methodology/Principal FindingsThe generation of ROS, cellular response to oxidative stress, and autophagy were investigated in PC3 prostate cancer cells by using drugs at sub-toxic doses. We evaluated whether PARP1-mediated apoptosis-inducing factor (AIF) release plays a role in apoptosis induced by the combination of the agents. Next, the effect of the combination of α-TOS, VK3 and AA on tumor growth was examined in nude mice. VK3 plus AA induced early ROS formation associated with induction of autophagy in response to oxidative stress, which was reduced by α-TOS, preventing the formation of autophagosomes. α-TOS induced mitochondrial destabilization leading to the release of AIF. Translocation of AIF from mitochondria to the nucleus, a result of the combinatorial treatment, was mediated by PARP1 activation. The inhibition of AIF as well as of PARP1 efficiently attenuated apoptosis triggered by the drug combination. Using a mouse model of prostate cancer, the combination of α-TOS, VK3 and AA was more efficient in tumor suppression than when the drugs were given separately, without deleterious side effects.Conclusions/Significanceα-TOS, a mitochondria-targeting apoptotic agent, switches at sub-apoptotic doses from autophagy-dependent survival of cancer cells to their demise by promoting the induction of apoptosis. Given the grim prognosis for cancer patients, this finding is of potential clinical relevance.

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“…Therefore, our endeavor was to explore the possibility that, elevation of cellular reactive oxygen species (ROS) level might be an approach to facilitate arsenic-induced apoptosis in cells intrinsically less sensitive to arsenic-monotherapy. Menadione, with pro-oxidative and anti-carcinogenic properties, was selected as the compound that can synergize with arsenic in the treatment of malignancies refractory to arsenic [11,12]. Although menadione is a relatively nontoxic compound, its semiquinone form is likely to increase cellular ROS through generation of super-oxides or hydrogen peroxide (H 2 O 2 ) [13].…”

Section: Introductionmentioning

confidence: 99%

Arsenic induced apoptosis in malignant melanoma cells is enhanced by menadione through ROS generation, p38 signaling and p53 activation

Chowdhury

Roychoudhury

et al. 2008

Apoptosis

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Vitamins C and K3 Sensitize Human Urothelial Tumors to Gemcitabine

Abstract: Vitamins C and K3 have significant antiproliferative and apoptotic effects when used in combination. This combination enhances the efficacy of gemcitabine against bladder cancer in vivo.

Cited by 37 publications

References 18 publications

A 12 Week, Open Label, Phase I/IIa Study Using Apatone^® for the Treatment of Prostate Cancer Patients Who Have Failed Standard Therapy

A 12 Week, Open Label, Phase I/IIa Study Using Apatone^® for the Treatment of Prostate Cancer Patients Who Have Failed Standard Therapy

Alpha-Tocopheryl Succinate Inhibits Autophagic Survival of Prostate Cancer Cells Induced by Vitamin K3 and Ascorbate to Trigger Cell Death

Arsenic induced apoptosis in malignant melanoma cells is enhanced by menadione through ROS generation, p38 signaling and p53 activation

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Vitamins C and K3 Sensitize Human Urothelial Tumors to Gemcitabine

Abstract: Vitamins C and K3 have significant antiproliferative and apoptotic effects when used in combination. This combination enhances the efficacy of gemcitabine against bladder cancer in vivo.

Cited by 37 publications

References 18 publications

A 12 Week, Open Label, Phase I/IIa Study Using Apatone® for the Treatment of Prostate Cancer Patients Who Have Failed Standard Therapy

A 12 Week, Open Label, Phase I/IIa Study Using Apatone® for the Treatment of Prostate Cancer Patients Who Have Failed Standard Therapy

Alpha-Tocopheryl Succinate Inhibits Autophagic Survival of Prostate Cancer Cells Induced by Vitamin K3 and Ascorbate to Trigger Cell Death

Arsenic induced apoptosis in malignant melanoma cells is enhanced by menadione through ROS generation, p38 signaling and p53 activation

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A 12 Week, Open Label, Phase I/IIa Study Using Apatone^® for the Treatment of Prostate Cancer Patients Who Have Failed Standard Therapy

A 12 Week, Open Label, Phase I/IIa Study Using Apatone^® for the Treatment of Prostate Cancer Patients Who Have Failed Standard Therapy