In our continuous studies of anticancer activity of steroidal
saponins from the rhizomes of Dioscorea collettii var. hypoglauca (Dioscoreaceae), methyl protoneogracillin (NSC-698793) and
gracillin (NSC-698787) were tested for cytotoxicity against human
cancer cell lines from
leukemia and eight solid
tumor diseases. As a result, methyl protoneogracillin was cytotoxic against all the test cell lines with GI(50) < 100 micro M, especially selectively against two
leukemia lines (CCRF-CEM and RPMT-8226), one
colon cancer line (KM12), two central nervous system (CNS)
cancer lines (SF-539 and U251), one
melanoma line (M14), one
renal cancer line (786-0), one
prostate cancer line (DU-145), and one
breast cancer line (MDA-MB-435), with GI(50) < or = 2.0 micro M.
Leukemia, CNS
cancer, and
prostate cancer were the most sensitive subpanels, while
ovarian cancer was the least sensitive subpanels. The preliminary toxicity studies showed that the maximum tolerant dose was 600 mg/kg for methyl protoneogracillin to mice.
Gracillin was cytotoxic against most cell lines with GI(50), TGI and LC(50) at micromolar levels, but no activity against EKVX (
non-small cell lung cancer), HT29 (
colon cancer), OVCAR-5 (
ovarian cancer), and SN12C (
renal cancer). Based on structure-activity relationship, C-25 R/S con fi guration was critical for
leukemia selectivity between methyl protoneogracillin and
methyl protogracillin. F-ring was critical to selectivity between furostanol (methyl protoneogracillin and
methyl protogracillin) and spirostanol (
gracillin)
saponins in this study. By an analysis of COMPARE software, no compounds in the NCI's database had similar mean graphs to those of methyl protoneogracillin and
gracillin, respectively, indicating potential novel mechanism(s) of action involved. Put all in together, methyl protoneogracillin has been selected as a potential anticancer candidate for hollow fi ber assay to nude mice, but
gracillin will not be pursued due to lack of selectivity against human
cancer diseases.