Discussion

Hypoxia is one of the key characteristics of solid tumors. The over-expression of azoreductase resulting from hypoxia can be used as a target to visualize hypoxic levels and a trigger of the drug release system in tumor treatment. In this work, we developed a near-infrared fluorescent probe YLOD, composed of a near-infrared fluorophore, an azo bond, and an analogue of the anti-tumor drug melphalan. In the presence of azoreductase, YLOD displayed a red emission at 620 nm and released the anti-tumor drug concomitantly, thus achieving the integrated effects of hypoxic imaging and tumor treatment. Furthermore, YLOD successfully inhibited the growth of solid tumors during the tumor suppression experiments in nude mice. Considering all the results, YLOD emerges as a new fluorescence tool that can quickly determine the location and the edges of a tumor, showing concrete potential in clinical cancer treatment.

Metabolic remodeling contributes to malignant cell progression. These cells take over the unique metabolic machinery for their continued survival. This metabolic reprogramming consists of upregulation of membrane-associated transporters; pH and redox homeostasis, favorable for driving metabolism; upregulated expression of ligand and receptor mediators. This can be accomplished by entrusting highly coordinated molecular patrons which contribute to the immortality of neoplastic cells. This opens a whole new window to exploit these metabolic liabilities in the treatment of cancer. In recent decades, chemotherapies targeting metabolism have proved an effective cure for cancer. Therefore, it is imperative to develop multitargeted therapeutic to attain formidable inhibition of tumor metabolism. Synthetic compounds and phytochemicals are potential inhibitors of enzymes in metabolic pathways which can regulate cancer growth. These inhibitors could be a promising strategy for the development of antineoplastic agents. Here, we discuss the deep-seated relation between malignancy and metabolism, centralizing on strategies through which these metabolic targets may turn into cancer’s flaw.

Multiple-target drugs may achieve better therapeutic effect via different pathways than single-target ones, especially for complex diseases. Tubulin and DNA are well-characterized molecular targets for anti-cancer drug development. A novel class of diaryl substituted 2H-azirines were designed based on combination of pharmacophores from Combretastatin A-4 (CA-4) and aziridine-type alkylating agents, which are known tubulin polymerization inhibitor and DNA damaging agents, respectively. The antitumor activities of these compounds were evaluated in vitro and 6h showed the most potent activities against four cancer cell lines with IC₅₀ values ranging from 0.16 to 1.40 μM. Further mechanistic studies revealed that 6h worked as a bifunctional agent targeting both tubulin and DNA. In the nude mice xenograft model, 6h significantly inhibited the tumor growth with low toxicity, demonstrating the promising potential for further developing novel cancer therapy with a unique mechanism.

Mitomycin C (MMC) is commonly used in patients with colorectal peritoneal metastases (CPM) treated with cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). MMC requires metabolic activation prior to exert its cytotoxic effect of which the main activating enzymes are NQO1 and POR. However, not all patients are able to activate MMC for example due to polymorphisms in the genes encoding these enzymes. The aim of this study was to investigate the association of NQO1∗2, NQO1∗3, and POR∗28 with the efficacy of CRS + HIPEC with MMC in patients with CPM.

A retrospective follow-up design was used to study genetic association in patients with histologically proven CPM treated with CRS + HIPEC with MMC with respect to peritoneal recurrence rate after 3 months (primary endpoint), after 6 months, disease-free survival and overall survival. Genetic polymorphisms NQO1∗2, NQO1∗3, and POR∗28 were tested for association.

A total of 253 patients were included. In NQO1∗3 carriers the peritoneal recurrence rate 3 and 6 months after HIPEC was significantly higher than in wild type patients, respectively 30.0% vs 3.8% (p = 0.009) and 40.0% vs 12.1% (p = 0.031). In line with these results, NQO1∗3 was associated with a shorter disease-free survival (HR 2.04, 95% CI [1.03–4.03]). There was no significant association with overall survival (HR 1.42, 95% CI [0.66–3.07]).

Carriership of the NQO1∗3 allele is associated with worse peritoneal recurrence rate and disease-free survival. These results suggest that individualization of patients treated with CRS + HIPEC based upon pharmacogenetics may be beneficial.

Two synthetic aziridinomitosenes (AZMs), Me-AZM and H-AZM, structurally related to mitomycin C (MC) were evaluated for their anticancer activity against six cancer cell lines (HeLa, Jurkat, T47D, HepG2, HL-60, and HuT-78) and tested for their DNA-modifying abilities in Jurkat cells. Cytotoxicity assays showed that Me-AZM is up to 72-fold and 520-fold more potent than MC and H-AZM, respectively. Me-AZM also demonstrated increased DNA modification over MC and H-AZM in alkaline COMET and Hoechst fluorescence assays that measured crosslinks in cellular DNA. Me-AZM and H-AZM treatment of Jurkat cells was found to sponsor significant DNA–protein crosslinks using a K-SDS assay. The results clearly indicate that the AZM C6/C7 substitution pattern plays an important role in drug activity and supports both DNA–DNA and DNA–protein adduct formation as mechanisms for inducing cytotoxic effects.

NAD(P)H: quinone oxidoreductase 1 (NQO1) is an obligate two-electron reductase and is highly expressed in many human solid cancers. Because NQO1 can be induced immediately after exposure to ionizing radiation, we aimed to develop an NQO1-targeted radiolabeled agent to establish a novel internal radiation therapy that amplifies the therapeutic effects when combined with external radiation therapy. We designed three NQO1-targeted radioiodinated compounds including two ether linkage compounds ([¹²⁵I]1 and [¹²⁵I]2) and a sulfide linkage compound ([¹²⁵I]3) based on the selective binding of indolequinone analogs to the active site of NQO1 by the stacking effect. These compounds were successfully prepared using an oxidative iododestannylation reaction with high radiochemical yields and purity. In NQO1-expressing tumor cells, [¹²⁵I]1 and [¹²⁵I]2 were readily metabolized to p-[¹²⁵I]iodophenol or m-[¹²⁵I]iodophenol and [¹²⁵I]I⁻, whereas over 85% of the initial radioactivity of [¹²⁵I]3 was observed as an intact form at 1 h after incubation. The cellular uptake of [¹²⁵I]3 was significantly higher than those of [¹²⁵I]1 and [¹²⁵I]2. The uptake of [¹²⁵I]3 was specific and was dependent on the expression of NQO1. These data suggest that the novel NQO1-targeted radioiodinated compound [¹²⁵I]3 could be used as a novel internal radiation agent for the treatment of cancer.