Antimetastatic and anti-invasive ability of phospho-ascorbyl palmitate through intracellular ascorbate enrichment and the resultant antioxidant action.
A lipophilic and auto-oxidation-resistant derivative of ascorbic acid (Asc), Asc-2-O-phosphate-6-O-palmitate (Asc2P6Plm), was shown to exert an invasion-inhibitory action as promptly as 30-40 min for 50% inhibition and 60-90 min for 80% inhibition after entering fibrosarcoma HT-1080 cells. Invasive inhibition of 95-97% was accomplished by Asc2P6Plm of doses exhibiting no cytotoxicity under the same conditions. Asc2P6Plm was dephosphorylated and esterolyzed to Asc, which enriched the intracellular Asc dose dependently in invasion-suppressed cells, contrasting with no detectable Asc in invasive cells fed without Asc2P6Plm. Intracellular dehydroAsc (DehAsc), unexpectedly, amounted to 1.02-1.65-fold as much as intracellular Asc, suggesting that invasive cells underwent oxidative stress, the repression of which resulted in both inhibition of tumor invasion and oxidative conversion of Asc to DehAsc. Correspondingly, intracellular oxidants fluorometrically detected with a redox indicator CDCFH were more abundant in invasive cells than in invasion-suppressed cells fed with Asc2P6Plm. Invasion inhibitory effects of Asc2P6Plm necessitated the extensive inhibition of the major gelatinases MMP-9 and MMP-2, as shown by zymography and Western blots, but did not necessitate direct expression of the metastasis suppressor gene nm23, taking as long as 6-18 h in contrast to a prompt action of Asc2P6Plm. Antimetastatic effects on melanoma B16BL6 cells were given dose dependently by intravenous administration or pretreatment with Asc2P6Plm. Thus, Asc2P6Plm is anticipated as an antimetastatic agent via the potent antioxidant activity.
Liu
J W
JW
Department of Cell Biochemistry, Hiroshima Prefectural University School of BioSciences, Shobara, Japan.
Nagao
N
N
Kageyama
K
K
Miwa
N
N
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism*; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D013997:Time Factors; D014407:Tumor Cells, Cultured
C403966:6-O-palmitol-ascorbate-2-O-phosphate; D000970:Antineoplastic Agents; D000975:Antioxidants; D017382:Reactive Oxygen Species; D020782:Matrix Metalloproteinases; D001205:Ascorbic Acid