“Combi‐targeting” mitozolomide: Conferring novel signaling inhibitory properties to an abandoned DNA alkylating agent in the treatment of advanced prostate cancer

Abstract

The results suggest that the superior cytotoxicity of JDF12 when compared with MTZ and JDF04R may be imputed to its potent EGFR-DNA targeting properties and confirm the ability of this novel strategy to confer EGFR targeting properties to a classical alkylator.

Expedient synthesis and anticancer evaluation of dual‐action 9‐anilinoacridine methyl triazene chimeras

“…The therapeutic activation of TMZ involves the spontaneous decomposition of a cyclic urea core, forming the unstable MTIC (Figure 1), which under physiologic conditions releases diazomethane (a very reactive DNA‐methylating agent). Therefore, we presumed that the protection of monomethyl amine intermediates using carbamate or amide biodegradable groups (Beckerab & Wurm, 2018) could result in molecular candidates better fit to release DNA‐methylating agents, similarly but with slower kinetics than TMZ (Fang et al., 2012). In addition, we realized that the N ‐protection of monomethyl triazene in the corresponding ortho ‐nitroaryls could help to overcome the formation of the un‐reactive benzotriazole upon reduction of NO 2 to NH 2 as mentioned above.…”

Potential Anticancer Mechanisms of a Novel EGFR/DNA-Targeting Combi-Molecule (JDF12) against DU145 Prostate Cancer Cells: An iTRAQ-Based Proteomic Analysis

“…Multiple transduction cascades including the Ras/MAPK pathway are believed to mediate cell survival following EGFR activation [ 17 ]. Expression of EGFR was significantly lower in JDF12-treated PCa cells after 24 h, while cells exposed to JDF12 for only 2 h did not show this response [ 8 ]. Further, no significant cell death was observed within 12 h. This temporal association suggests that EGFR downregulation by JDF12 may be required to induce apoptosis, although the additional DNA-alkylating effect may also contribute.…”

“…In situ, JDF12 is hydrolyzed to JDF04R, which can inhibit the phosphorylation of EGFR and activation of isolated EGFR tyrosine kinase. In addition, JDF12 is hydrolyzed to a DNA-alkylating agent [ 8 ]. Subsequent studies showed that JDF12 exhibited not only stronger anticancer effects than single drugs or joint use of two drugs at equivalent doses, but also better toxicity profiles and lower drug resistance rate [ 9 , 10 ].…”