Antitumor and anti-invasive effects of diverse new macrocyclic lactones, alkylolides and alkenylolides, and their enhancement by hyperthermia.
Alkylolides and alkenylolides of 198-254 Da such as hexadecan-16-olide and 9-hexadecen-16-olide were chemically synthesized in the present study as new macrocyclic lactones that are structurally different from widespread natural macrocyclic lactones including bryostatin (887 Da) and rhizoxin (613 Da), and were investigated for antitumor activity to Ehrlich ascites tumor cells by mitochondrial dehydroganase-based WST-1 assay and dye-exclusion assay. Of the alkylolides having 12, 15 or 16 carbon-atoms (D12:0, P15:0 or H16:0) and alkenylolides having 15 or 16 carbon-atoms with a double bond (P15:1 or H16:1), H16:0 was the most carcinostatic when administered at 37 degrees C for 20 h, with cell deformation and microvillus disappearance as detected by scanning electron microscopy. The carcinostatic activity was increased markedly for H16:0 and P15:0 when the administration period was prolonged to 72 h, but was not enhanced by intramolecular introduction of a double bond for P15:1 or H16:1. Hyperthermia at 42 degrees C for 30 min additively intensified the carcinostatic activity for H16:0 and P15:0, but scarcely for D12:0, and intensified the alkenyloides P15:1 and H16:1 only upon the subsequent 72-h treatment. Invasion of human fibrosarcoma HT-1080 cells through the reconstituted basement membrane was inhibited by alkyl- and alkenylolides even after the short-term exposure at 25 microM for 3 h without diminishing the cell viability. H16:0 also exhibited the most inhibitory activity to tumor invasion in addition to the highest carcinostatic activity. Both inhibitions were promoted by combination with hyperthermia. Thus diverse alkyl-/alkenylolides, may be potent multi-applicable anticancer agents in terms of either dual inhibitory activities against both tumor progression and invasion or hyperthermia-combined therapy.
Tanaka
Hiroshi
H
Osaka Butsuryo College, 3-33 Otorikita-cho, Nishi-ku, Sakai, Osaka 593-8328, Japan.
Kageyama
Katsuhiro
K
Kusumoto
Kumiko
K
Asada
Ryoko
R
Miwa
Nobuhiko
N
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D054713:Bryostatins / Q000494:pharmacology; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D006979:Hyperthermia, Induced; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D018942:Macrolides / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D054713:Bryostatins; D007783:Lactones; D018942:Macrolides; C046785:bryostatin 1; C041443:rhizoxin