Abstract |
Naturally occurring sesquiterpene lactones and their semisynthetic derivatives, such as the O = C-C = CH-bearing helenalin and its esters, have been shown to demonstrate potent cytotoxicity against the growth of murine L1210 lymphoid leukemia and human Tmolt3 leukemia, colon adenocarcinoma, HeLaS3, lung bronchogenic, KB, osteosarcoma, and glioma cells. The modes of action of helenalin in L1210 cells are the inhibition of DNA, RNA, and protein syntheses. This study confirms that thiol bearing enzymes of nucleic acid metabolism were significantly inhibited, e.g. DNA polymerase alpha, IMP hydrogenase, and ribonucleoside reductase. The addition of GSH to the reaction medium demonstrated total recovery of L1210 ribonucleoside reductase activity. Helenalin reduced cellular GSH levels in L1210 cells. Helenalin also reduced all four pool levels of d(NTP)s which would account for part of the observed inhibition of DNA synthesis. Reductions in the ribonucleotide pool levels were also generally evident after drug treatment. Thus, the sesquiterpene lactones appear to have more than one mode of action in L1210 cells. All of the modes of actions of helenalin are feasible mechanisms to lower nucleic acid synthesis and cause cell death of the L1210 leukemia cells.
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Authors | A A Grippo, I H Hall, H Kiyokawa, O Muraoka, Y C Shen, K H Lee |
Journal | Drug design and discovery
(Drug Des Discov)
Vol. 8
Issue 3
Pg. 191-206
(Feb 1992)
ISSN: 1055-9612 [Print] Switzerland |
PMID | 1525302
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Antineoplastic Agents, Phytogenic
- Deoxyribonucleotides
- Esters
- Lactones
- Ribonucleotides
- Sesquiterpenes
- Sesquiterpenes, Guaiane
- helenalin
- DNA-Directed DNA Polymerase
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Topics |
- Animals
- Antineoplastic Agents, Phytogenic
(pharmacology, toxicity)
- DNA-Directed DNA Polymerase
(drug effects, metabolism)
- Deoxyribonucleotides
(metabolism)
- Esters
(pharmacology)
- Humans
- Lactones
(pharmacology)
- Leukemia L1210
(drug therapy, enzymology, metabolism)
- Mice
- Ribonucleotides
(metabolism)
- Sesquiterpenes
(pharmacology, toxicity)
- Sesquiterpenes, Guaiane
- Tumor Cells, Cultured
(drug effects)
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