Tetra- O -methyl nordihydroguaiaretic acid induces growth arrest and cellular apoptosis by inhibiting Cdc2 and survivin expression

Abstract

We previously reported that Sp1-dependent Cdc2 gene expression is inhibited by tetra-O-methyl nordihydroguaiaretic acid (M 4N) and that M 4N is likely responsible for causing growth arrest in M4N-treated transformed C3 cells. Here, we show that after M 4N treatment and cell-cycle arrest, expression of the Sp1-dependent survivin gene, a member of the inhibitor of apoptosis family, is also suppressed, and the mitochondrial apoptotic pathway is activated. To confirm that inhibition of Cdc2 and survivin gene expression is necessary for M 4N-induced growth arrest and apoptosis, we tested the effect of adding Cdc2 and survivin back to M 4N-treated cells. Cell division was transiently restored in the presence of M 4N after transfection of an exogenous Cdc2 gene copy under the control of the Sp1-independent cytomegalovirus promoter. Caspase-3 activation was also reduced by 50% and 75% in transiently and stably survivin-transfected C3 cells, respectively. The results suggest that M 4N induces growth arrest and apoptosis by suppressing Cdc2 and survivin expression, which constitutes the cellular basis of its antitumoric action.

p21WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia

“…Various models of ALL were utilized, including patientderived xenografts (PDXs) with epigenetically silenced p21 WAF1 in p53-functional T-ALL samples, transient siRNA and stable lentiviral knockdown of p21 WAF1 expression in BCP-ALL cell lines and pharmacological modulation of p21 WAF1 induction by terameprocol. 41 Our results show that p21 WAF1 exerts a significant influence on the kinetics of apoptosis mediated by chemotherapeutic drugs, but does not markedly influence in vitro sensitivity to p53-inducing agents or non-apoptotic characteristics of cell death.…”

“…41 HDAC inhibitors such as vorinostat have been shown to induce p21 WAF1 through Sp1 activation. 51 In these experiments, the selectivity of terameprocol in modulating p21 WAF1 expression through Sp1 was confirmed as this drug inhibited p21 WAF1 induction mediated by vorinostat but had no effect on etoposide mediated p21 WAF1 expression.…”

“…38,39 With p21 WAF1 having an anti-apoptotic role in response to certain cytotoxic agents, inhibition of p21 WAF1 has been considered as a strategy for cancer treatment to sensitize cells toward apoptosis after chemotherapy exposure. 40 The Sp1 inhibitor, terameprocol, has been previously demonstrated to inhibit p21 WAF1 expression 41 and can be utilized to demonstrate any impact of p21 WAF1 inhibition on cell death.…”

Mechanistic and Structural Studies of Apoform, Binary, and Ternary Complexes of the Arabidopsis Alkenal Double Bond Reductase At5g16970

“…Crystals of both ternary complexes were obtained by mixing AtDBR1 with NADP ϩ /p-coumaryl aldehyde (6) and by soaking the AtDBR1/NADP ϩ binary complex crystals in a solution containing 4-HNE (15), respectively. The apoform of AtDBR1 was determined at 2.5 Å resolution by the molecular replacement method using coordinates of the aforementioned 12-HD/PGR (PDB code 1V3V) from guinea pig (C. porcellus) (29), which shows 56/41% similarity/identity to AtDBR1 (Table 1).…”

“…For example, this pathway results in formation of the potent antiviral agent, podophyllotoxin (1), which also serves as a semi-synthetic source of the highly successful cancer chemotherapeutic treatments, teniposide, etoposide, and Etopophos (2)(3)(4). Other examples include: matairesinol and secoisolariciresinol, which are some of the dietary sources of the "mammalian" lignans, enterolactone/enterodiol, these being protective against the onset of various malignancies (5); the nordihydroguaiaretic acid derivatives, which show considerable promise against refractory cancers of the neck and the head (6); the potent antioxidant chlorogenic acid, which has well documented anticancer properties (7,8), as well as reducing the risk of cardiovascular disease (9); and the monomeric allyl/propenyl phenols such as chavicol and eugenol, which have well known antibacterial and analgesic properties (10). Other medicinally important phenylpropanoid (acetate) pathway metabolites include dihydroconiferyl alcohol (1; Fig.…”