Cytotoxic activity of deferiprone, maltol and related hydroxyketones against human tumor cell lines.
Hydroxyketone chelators, deferiprone (HK1), maltol (HK3) and their related compounds (HK2, 4-8), were characterized for their cytotoxic profiles against oral human normal and tumor cells. Most hydroxyketones except HK6 showed relatively higher tumor-specific cytotoxicity. Deferiprone (HK1), which showed the highest tumor specificity, had 10 times higher cytotoxicity than maltol (HK3) in both human promyelocytic leukemia HL-60 and human oral squamous cell carcinoma HSC-2 cell lines. The cytotoxic activity of HK1 against HL-60 and HSC-2 cells was reduced in the presence of FeCl3, while that of HK3 was significantly increased by FeCl3. Agarose gel electrophoresis showed that HK1 induced internucleosomal DNA fragmentation in HL-60 cells, but the addition of FeCl3 inhibited the DNA fragmentation. HK3 did not induce DNA fragmentation in HL-60 cells, regardless of the presence or absence of FeCl3. In HSC-2 cells, HK1 and 3 did not induce DNA fragmentation in the presence or absence of FeCl3. Colorimetric protease assay showed that HK1 activated the caspase 3, 8 and 9 in HL-60 cells. On the other hand, HK3 did not activate the caspase 3, 8 and 9 in HL-60 cells, but activated the caspase 3 only slightly in the presence of FeCl3. HK1 and 3 also activated the caspase 3, 8 and 9 in HSC-2 cells, but to a lesser extent. The present study suggested that the antitumor activity of hydroxyketones may be modified by Fe3+ concentration.
Yasumoto
Eiji
E
Department of Dental Pharmacology, Meikai University School of Dentistry, Sakado, Saitama, Japan.
Nakano
Kensuke
K
Nakayachi
Tohru
T
Morshed
Sufi Reza Md
SR
Hashimoto
Ken
K
Kikuchi
Hirotaka
H
Nishikawa
Hirofumi
H
Kawase
Masami
M
Sakagami
Hiroshi
H
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000187:drug effects; D000077543:Deferiprone; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007659:Ketones / Q000737:chemistry / Q000494:pharmacology*; D008898:Mimosine / Q000494:pharmacology; D039821:Monoterpenes / Q000494:pharmacology; D009062:Mouth Neoplasms / Q000188:drug therapy; D011728:Pyridones / Q000494:pharmacology*; D011753:Pyrones / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014334:Tropolone / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D002614:Chelating Agents; D007659:Ketones; D039821:Monoterpenes; D011728:Pyridones; D011753:Pyrones; D000077543:Deferiprone; C008316:maltol; D008898:Mimosine; C011890:kojic acid; D014334:Tropolone; D020169:Caspases; C009479:beta-thujaplicin