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.