Hypoxia-selective growth inhibition of cancer cells by furospinosulin-1, a furanosesterterpene isolated from an Indonesian marine sponge.
It is generally accepted that cancer cells, which have adapted to the hypoxic environments in tumor tissues, aggravate cancer pathology by promoting tumor growth, angiogenesis, metastasis, and drug resistance. Therefore, compounds that selectively inhibit the growth of tumor cells in hypoxic environments are expected to provide new leads for promising anticancer drugs. Furospinosulin-1, a marine-sponge-derived furanosesterterpene, exhibited selective antiproliferative activity against DU145 human prostate cancer cells under hypoxic conditions in concentrations ranging from 1 to 100 μM. Furospinosulin-1 also demonstrated antitumor activity at 10-50 mg kg(-1) oral administration in a mouse model inoculated with sarcoma S180 cells. Mechanistic analysis revealed that furospinosulin-1 suppresses transcription of the insulin-like growth factor-2 gene (IGF-2), which is selectively induced under hypoxic conditions through prevention of the binding of nuclear proteins to the Sp1 consensus sequence in the IGF-2 promoter region.
Arai
Masayoshi
M
Graduate School of Pharmaceutical Sciences, Osaka University, Yamada-oka 1-6, Suita, Osaka 565-0871, Japan. araim@phs.osaka-u.ac.jp
Kawachi
Takashi
T
Setiawan
Andi
A
Kobayashi
Motomasa
M
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use*; D001688:Biological Products / Q000008:administration & dosage / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005663:Furans / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008297:Male; D051379:Mice; D011161:Porifera / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D054830:Sesterterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use*; D013729:Terpenes / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001688:Biological Products; D005663:Furans; D054830:Sesterterpenes; D013729:Terpenes; C555679:furospinosulin-1; D007335:Insulin-Like Growth Factor II