Balanitin-6 and -7: diosgenyl saponins isolated from Balanites aegyptiaca Del. display significant anti-tumor activity in vitro and in vivo.
Balanites aegyptiaca is a widely distributed African plant of medicinal interest containing a number of cytotoxic and cytostatic compounds. The studies reported here have attempted to further characterize the anti-cancer activity of a mixture of steroidal saponins: balanitin-6 (28%) and balanitin-7 (72%) isolated from Balanites aegyptiaca kernels. The balanitin-6 and -7 mixture (henceforth referred to as bal6/7) has demonstrated appreciable anti-cancer effects in human cancer cell lines in vitro. Bal6/7 displayed higher anti-proliferative activity than etoposide and oxaliplatin, although the mixture was appreciably less active than SN38 and markedly less active than taxol. Bal6/7 demonstrated highest activity against A549 non-small cell lung cancer (NSCLC) (IC(50), 0.3 microM) and U373 glioblastoma (IC(50), 0.5 microM) cell lines. The current study has further indicated that bal6/7 is more a cytotoxic compound than a cytostatic one. However, Bal6/7 does not appear to mediate its anti-proliferative effects by inducing apoptotic cell death. Computer-assisted cellular imaging has revealed that bal6/7 does not induce detergent-like effects in A549 NSCLC and U373 glioblastoma unlike certain saponins. Furthermore there is indication that its in vitro anti-cancer activities result at least partly from depletion of [ATP]i, leading in turn to major disorganization of actin cytoskeleton, ultimately resulting in the impairment of cancer cell proliferation and migration. In contrast to a number of natural products acting as anti-cancer agents, bal6/7 does not induce an increase in intra-cellular reactive oxygen species. In vivo, bal6/7 increased the survival time of mice bearing murine L1210 leukemia grafts to the same extent reported for vincristine. These preliminary in vivo data suggest that it may be possible to generate novel hemi-synthetic derivatives of balanitin-6 and -7 with potentially improved in vitro and in vivo anti-cancer activity and reduced in vivo toxicity, thus markedly improving the therapeutic ratio.
Gnoula
Charlemagne
C
Laboratoire de Chimie Bioanalytique, de Toxicologie et de Chimie Physique Appliquée, Institut de Pharmacie, Université Libre de Bruxelles (ULB), 1050 Brussels, Belgium.
Mégalizzi
Véronique
V
De Nève
Nancy
N
Sauvage
Sébastien
S
Ribaucour
Fabrice
F
Guissou
Pierre
P
Duez
Pierre
P
Dubois
Jacques
J
Ingrassia
Laurent
L
Lefranc
Florence
F
Kiss
Robert
R
Mijatovic
Tatjana
T
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D032430:Balanites / Q000737:chemistry*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004144:Diosgenin / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D017382:Reactive Oxygen Species / Q000378:metabolism; D012503:Saponins / Q000494:pharmacology* / Q000633:toxicity
D000972:Antineoplastic Agents, Phytogenic; D017382:Reactive Oxygen Species; D012503:Saponins; C527364:balanitin 6; C121204:balanitin 7; D000255:Adenosine Triphosphate; D004144:Diosgenin