Antitumor Properties of Podophyllotoxin and Related Compounds

Abstract

The lignan family of natural products includes compounds with important antineoplastic and antiviral properties such as podophyllotoxin and two of their semisynthetic derivatives, etoposide and teniposide. The latter are included in a wide variety of cancer chemotherapy protocols. Due to these biological activities, lignans, and especially cyclolignans, have been the objective of numerous studies focused to prepare better and safer anticancer drugs. The mechanism by which podophyllotoxin blocks cell division is related to its inhibition of microtubule assembly in the mitotic apparatus. However, etoposide and teniposide were shown not to be inhibitors of microtubule assembly which suggested that their antitumor properties were due to another mechanism of action, via their interaction with DNA and inhibition of DNA topoisomerase II. Other podophyllotoxin derivatives has also been reported which retained or even improved the cytotoxic activity, but these were weak inhibitors of topoisomerase II in vitro; the data revealed that such analogs exhibit a different, as yet unknown, mechanism of action. The main deficiency of these compounds is their cytotoxicity for normal cells and hence side effects derived from their lack of selectivity against tumoral cells. In this regard it is necessary to investigate and prepare new more potent and less toxic analogs, that is, with better therapeutic indices. It is well accepted from structure-activity studies in this field that the trans-lactones are more potent as antineoplastics than the cis-lactones. Not only the configuration of the D ring is an important factor for high cytotoxic activity, but also a quasi-axial arrangement of the E ring is necessary. On this basis, studies on lignans have been addressed to modify the lactone moiety and prepare analogs with heteroatoms at different positions of the cyclolignan skeleton. Our group has been working during the last few years on chemical transformations of podophyllotoxin and analogs and we have prepared a large number of cyclolignan derivatives some of which display potent antiviral, immunosuppressive and cytotoxic activities. We have reported several new cytotoxic agents with nitrogen atoms at C-7 or C-9 or at both C-7 and C-9: imine derivatives, oxime derivatives, pyrazoline-, pyrazo- and isoxazoline-fused cyclolignans. At present, we are preparing mainly new compounds by modifications of the A and E cyclolignan-rings. They are being tested on cultures of different tumoral cell lines (P-388 murine leukemia, A-549 human lung carcinoma, HT-29 human colon carcinoma and MEL-28 human melanoma) and some of them have shown an interesting and selective cytotoxicity.

Flaxseed attenuates the tumor growth stimulating effect of soy protein in ovariectomized athymic mice with MCF‐7 human breast cancer xenografts

“…by inhibiting angiogenesis, 45 tyrosine kinases via IGF-1 receptor and c-erbB2/HER2/neu mediated pathways, 46 COX-2 expression 47 or DNA topoisomerase II. 48 Ovariectomized athymic mice with MCF-7 cells has limitations as an animal model to determine the effect of hormonally active compounds on postmenopausal breast cancer. While circulating estrogen levels are low in postmenopausal women, breast tumors still grow because of estrogen synthesis that takes place in the tumors and peripheral tissues.…”

Chemical constituents and biological activities of species of Justicia: a review

“…Lignans also show antiangiogenic, antileishmanial, antifungal, hypolipidemic, antiasthmatic (Vasilev & Ionkova, 2005), antiviral (Asano et al, 1996), antineoplastic (Gordaliza et al, 2000), antifeedant (Bedoya et al, 2008), insecticidal, cardiotonic, antidepressant (Ghosal et al, 1979), analgesic, antiplatelet (Chen et al, 1996), and anti-inflammatory (Navarro et al, 2004) indications, as well as activity as lipid peroxidation inhibitors. Potent anti-inflammatory activities were described for lignan glycosides isolated from J. ciliata (Day et al, 2000) and phenolic compounds isolated from J. prostrata (Sanmugapriya et al, 2005b).…”

Plant-derived anticancer agents: a promising treatment for bone metastasis

“…Etoposide and teniposide are used in the treatment of lymphomas, as well as acute leukemia and smallcell lung, testicular, ovarian and bladder cancers. 4 In 1960, the United States National Cancer Institute (NCI) initiated an extensive plant collection program leading to the discovery of many novel chemotypes including taxanes and camptothecins. The taxanes were isolated from Taxus brevifolia and other conifers from the genus Taxus.…”