Inhibition of human HT29 colon carcinoma growth in vitro and in vivo by swainsonine and human interferon-alpha 2.
Swainsonine, a plant alkaloid and potent inhibitor of Asn-linked oligosaccharide processing, has previously been shown to inhibit organ colonization by metastatic murine tumor cells and to inhibit the growth of transformed fibroblasts in soft agar. In this report, we show that swainsonine has antiproliferative activity against human tumor cells growing in tissue culture and as tumor xenografts in nude mice. The antiproliferative activity of swainsonine was additive with that of human interferon-alpha 2 (HuIFN-alpha 2) in cultures of HT29 colon carcinoma, SN12 renal carcinoma, and A375 melanoma cells. In vivo, the growth rate of HT29m human colon carcinoma tumors in athymic nude mice was reduced by supplementing their drinking water with swainsonine (49%) or by administering HuIFN-alpha 2 systemically (53%); combining these treatments reduced tumor growth by 78%. Combining swainsonine and HuIFN-alpha 2 treatments enhanced the activity of the interferon-inducible enzyme 2',5'-oligoadenylate [2',5'-oligo(A)] synthetase in HT29m tumors compared to that observed in tumors from mice treated with interferon alone. In vitro, swainsonine enhanced interferon-dependent induction of 2',5'-oligo(A) synthetase activity in low-density cultures of HT29m cells. However, swainsonine alone did not stimulate 2',5'-oligo(A) synthetase activity in vivo or in vitro, indicating that the antiproliferative effect of swainsonine is independent of interferon production. The results suggest that in addition to the previously reported antimetastatic activity of swainsonine, the plant alkaloid has antiproliferative activity that is independent from, but additive with, that of interferon in vivo and in vitro.
Dennis
J W
JW
Division of Cancer and Cell Biology, Mt. Sinai Hospital Research Institute, Toronto, ON, Canada.
Koch
K
K
Beckner
D
D
D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism; D000470:Alkaloids / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D006131:Growth Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D007370:Interferon Type I / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D017026:Swainsonine; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D006131:Growth Inhibitors; D007370:Interferon Type I; D015088:2',5'-Oligoadenylate Synthetase; D017026:Swainsonine