Antitumor effect of pharmacologic ascorbate in the B16 murine melanoma model

Serrano, Oscar K.; Parrow, Nermi L.; Violet, Pierre-Christian; Yang, Jacqueline; Zornjak, Jennifer; Basseville, Agnès; Levine, Mark

doi:10.1016/j.freeradbiomed.2015.06.032

Cited by 24 publications

(20 citation statements)

References 52 publications

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“…E, Survival analysis of the mice depicted in D. w/o, without; vit C, vitamin C; 3p, 3pRNA; mm, millimeter; ns, not significant; Ã , P < 0.05; ÃÃ , P < 0.01; ÃÃÃ , P < 0.001 by unpaired Student t test for B-D and by log-rank (Mantel-Cox) test for E. Means and SEM are shown. melanoma appears to be sensitive to the direct cellular effects of vitamin C, as it has been linked to cell-cycle arrest and inhibition of VEGF production in B16.F10 for example (37,38). Moreover, vitamin C can directly induce caspase-8-dependent apoptosis in (murine) melanoma cells (39) as well as cell cycle arrest (40).…”

Section: Discussionmentioning

confidence: 99%

RIG-I Resists Hypoxia-Induced Immunosuppression and Dedifferentiation

Engel

Brügmann

Lambing

et al. 2017

Cancer Immunology Research

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A hypoxic tumor microenvironment is linked to poor prognosis. It promotes tumor cell dedifferentiation and metastasis and desensitizes tumor cells to type-I IFN, chemotherapy, and irradiation. The cytoplasmic immunoreceptor retinoic acid-inducible gene-I (RIG-I) is ubiquitously expressed in tumor cells and upon activation by 5'-triphosphate RNA (3pRNA) drives the induction of type I IFN and immunogenic cell death. Here, we analyzed the impact of hypoxia on the expression of RIG-I in various human and murine tumor and nonmalignant cell types and further investigated its function in hypoxic murine melanoma. 3pRNA-inducible RIG-I-expression was reduced in hypoxic melanoma cells compared with normoxic controls, a phenomenon that depended on the hypoxia-associated transcription factor HIF1α. Still, RIG-I functionality was conserved in hypoxic melanoma cells, whereas responsiveness to recombinant type-I IFN was abolished, due to hypoxia-induced loss of type I IFN receptor expression. Likewise, RIG-I activation in hypoxic melanoma cells, but not exposure to recombinant IFNα, provoked melanocyte antigen-specific CD8 T-cell and NK-cell attack. Scavenging of hypoxia-induced reactive oxygen species by vitamin C restored the inducible expression of RIG-I under hypoxia , boosted anti-melanoma NK- and CD8 T-cell attack, and augmented 3pRNA antitumor efficacy These results demonstrate that RIG-I remains operational under hypoxia and that RIG-I function is largely insensitive to lower cell surface expression of the IFNα receptor. RIG-I function could be fortified under hypoxia by the combined use of 3pRNA with antioxidants..

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Section: Discussionmentioning

confidence: 99%

RIG-I Resists Hypoxia-Induced Immunosuppression and Dedifferentiation

Engel

Brügmann

Lambing

et al. 2017

Cancer Immunology Research

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“…B16-F10 cells in C57BL/6 mice is a well-established and extensively employed model for the study of drug effects on malignant melanoma both in vitro and in vivo. 31–35 Although the experimental metastasis model (introduction of tumor cells directly into the vasculature such as tail vein) has its limitation vs a spontaneous metastasis model (metastasis formed through inoculation of tumor cells into tissues), 36 the number of pulmonary metastasis in mice that were tail vein injected with tumors cells, like melanoma, is known to directly correlate to the malignancy of a cell line and the effectiveness of an antineoplastic drug. 36 Therefore, the results from this investigation are informative and provide the basis for further investigation.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Antimetastatic Effect of Glutathione Disulfide Liposomes

Sadhu

Wang

Dachineni

et al. 2017

Cancer�Growth�Metastasis

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Cancer metastasis is the major cause of cancer mortality. Despite extensive research efforts, effective treatment for cancer metastasis is still lacking. Cancer metastasis involves 4 essential steps: cell detachment, migration, invasion, and adhesion. Detachment is the first and required step for metastasis. Glutathione disulfide (GSSG) is derived from the oxidation of glutathione (GSH), which is present in biological systems in millimolar concentration. Although GSSG is commercially available, the impact of GSSG on cell functions/dysfunctions has not been fully explored due to the fact that GSSG is not cell membrane permeable and a lack of method to specifically increase GSSG in cells. We have developed GSSG liposomes that effectively deliver GSSG to cells. Unexpectedly, cells treated with GSSG liposomes were resistant to detachment by trypsinization. This observation led to the investigation of the antimetastatic effect of GSSG liposomes. Our data demonstrate that GSSG liposomes at 1 mg/mL completely blocked cell detachment and migration, and significantly inhibited cancer cell invasion. Aqueous GSSG showed no such effect, confirming that the effects on cell detachment, migration, and invasion were caused by the intracellular delivery of GSSG. An in vivo experiment with a murine melanoma experimental metastasis model showed that GSSG liposomes prevented melanoma lung metastasis. The unique antimetastatic mechanism through the effects on detachment and migration, and effective in vitro and in vivo metastasis inhibition, warrants further investigation of the GSSG liposomes as a potential treatment for cancer metastasis.

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“…5 • At least a dozen biochemical, metabolic, and biological anticancer mechanisms of vitamin C have been documented. [6][7][8][9][10] Vitamin C has been used for more than 40 years in patients with cancer, and although it has not been incorporated into medical guidelines, it has been documented in published studies to be very safe. A US survey of 172 practitioners who had used intravenous vitamin C with a total of 20,009 patients concluded that, other than the known precautions, high-dose intravenous vitamin C appears to be remarkably safe.…”

Section: Vitamin C Researchmentioning

confidence: 99%