p53-independent apoptosis mediated by tachpyridine, an anti-cancer iron chelator

Abstract

Iron is involved in essential biochemical reactions ranging from respiration to DNA synthesis. Consequently, iron deprivation has been proposed as a strategy for inhibition of tumor cell growth. We recently described a novel iron chelator, tachypyridine [N,N',N"-tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane], and demonstrated that it not only inhibited growth of cultured tumor cells, but was actively cytotoxic. Here we explore the mechanisms underlying tachpyridine cytotoxicity. Using several criteria, including time-lapse video microscopy, DNA staining and TUNEL assays, tachpyridine was shown to specifically induce apoptotic cell death. Further, unlike numerous cytotoxic chemotherapeutic drugs which induce apoptosis by activating p53-dependent pathways, tachpyridine-mediated cell death did not require p53 activation. Although immunoblotting revealed rapid accumulation of p53 following treatment with tachpyridine, p21(WAF1) was not induced. Further, neither cytotoxicity nor apoptosis required p53. p53 null human lung cancer H1299 cells transfected with an ecdysone-inducible p53 exhibited equivalent sensitivity to tachpyridine in the presence and absence of p53, demonstrating the lack of requirement for p53 in an isogenic cell system. Further, time-lapse video microscopy and TUNEL assays demonstrated that both p53 null and p53 wild-type cells underwent apoptotic cell death in response to tachpyridine. In addition, in 55 human cancer cell lines the mean GI(50) of tachpyridine in cells with mutant p53 was virtually identical to the GI(50) in cells with wild-type p53. These results demonstrate that tachpyridine initiates an apoptotic mode of cell death that does not require functional p53. Since over 50% of human tumors contain a functionally defective p53 that reduces sensitivity to commonly used chemotherapeutic agents, such as etoposide and cisplatin, the ability of tachpyridine to induce apoptosis independently of p53 may offer an advantage in anti-tumor therapy.

A novel antioxidant 3-O-Caffeoyl-1-methylquinic acid enhances ultraviolet A-mediated apoptosis in immortalized HaCaT keratinocytes via Sp1-dependent transcriptional activation of p21WAF1/Cip1

“…As shown in Figure 8a, the level of ferritin was found to be decreased by MCGA3 treatment, which is evident at 8 h after treatment, whereas TfR1 protein level was more rapidly elevated by MCGA3 treatment, which is evident at 2 h and gradually increased in a timedependent manner. Studies have shown cross-link between intracellular iron deprivation-induced hypoxia and p53-independent p21 upregulation (Abeysinghe et al, 2001;Baby et al, 2003). Similarly, our results also shows, MCGA3 treatment induces p21 and TfR1 protein levels in timedepended manner (Figures 4a and 8a).…”

“…Therefore, we initially hypothesized that the ROSscavenging and iron-chelating potential of MCGA3 may play a role in the p21 induction by providing a hypoxic condition. Recent studies (Carmeliet et al, 1998;Abeysinghe et al, 2001;Goda et al, 2003) have shown that HIF-1a-involved p21 transcriptional activation without p53 transcriptional function. Our p21-promoter assays clearly reflect the p53-independent, Sp1-dependent transcriptional activation of p21 by MCGA3.…”

A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics

“…The effects of chelators at inhibiting tumor growth are probably mediated through their action on many unique targets (e.g., Nip1, etc.) (19,37,38) and cannot be explained only by increased Ndrg1.…”

“…Because numerous tumors contain functionally defective p53, anticancer agents that induce apoptosis in a p53-independent manner must be developed (19)(20)(21)(22). Hence, we examined whether the DpT chelators can act independent of p53 apoptotic pathways.…”

Prostate Cancer Evaluation: Design, Synthesis, and Evaluation of Novel Enzyme-Activated Proton MRI Contrast Agents

“…[48] Tumor cells, as compared with their normal counterparts, frequently exhibit increased uptake and utilization of iron, as evidenced by an increase in transferrin receptors at the cell surface. [49][50][51] Additionally, cancer cells are sensitive to the effects of iron chelators because of the critical requirement for iron in proteins that play essential roles in DNA synthesis and energy production. [52,53] Such studies have led to iron chelation therapy to clinically treat some tumors.…”