Hydrogen peroxide stimulates gold nanorods, paclitaxel, for cancer treatment

Paclitaxel has found its way into many uses as an antiproliferative, including in the human circulatory system, but it’s use in oncology is somewhat limited by the ability of cancers to develop resistance strategies. Gold nanorods, in contrast, have been used in cancer treatment but have suffered for want of accuracy when used in photothermal therapy. However, researchers in China believe a form of hydrogen peroxide can offset these deficiencies and create a nanomaterial that can take a hard line against cancer. This entails development of a hydrogen peroxide (H2O2)-activated nanomaterial consisting of lipid vesicles, paclitaxel and gold nanorods coated in silver shells. The shells can be “etched” by endogenous hydrogen peroxide in the tumor microenvironment, at which point the surfaces of the gold nanorods are sufficiently exposed to react to photonic energy. The oxygen created by the interaction between the hydrogen peroxide and the silver shells breaks down the lipid vesicles, thus liberating both the gold nanorods and the paclitaxel. In animal studies, this approach demonstrated extensive necrosis and apoptosis, the authors said, providing yet another nanoweapon in the war on cancer. These results are explained in more detail in RSC Advances.

Oncometabolites mask DNA repair signals

Researchers at Yale University have demonstrated that mutations in metabolic enzymes made tumor cells sensitive to DNA repair inhibition via their effects on chromatin methylation. Metabolic deregulation is one of the hallmarks of cancer. Mutations in several metabolic enzymes also confer sensitivity to DNA repair inhibition by poly-(ADP-ribose) polymerase (PARP) inhibitors, through previously unknown molecular mechanisms. The Yale team showed that oncometabolites inhibited an epigenetic enzyme, lysine demethylase, leading to general hypermethylation of lysines. Trimethylation of lysines adjacent to DNA breaks is normally a signal for homology-directed repair machinery, and the hypermethylation due to inhibition of lysine demethylase essentially drowned out the trimethylated lysines near DNA breaks, leading to reduced recruitment of the DNA repair proteins ATM and TIP60. The authors wrote that “these findings provide a mechanistic basis for oncometabolite-induced HDR suppression and may guide effective strategies to exploit these defects for therapeutic gain.” Their work was published in the June 4, 2020, issue of Nature.

Stress-induced mutagenesis leads to cancer drug resistance

Researchers at the Garvan Institute of Medical Research have demonstrated that mTOR activation in cancer cells led to stress-induced mutagenesis. Tumors’ increased mutation rates help them develop resistance to drugs, but lethal mutation rates also underpin the effects of both chemotherapies and radiation. In their work, the authors demonstrated that cancer cells treated with targeted therapies had increased mutation rates, even if the therapies did not directly target DNA repair. Mechanistically, mTOR activation in tumor cells increased mutation rates by inducing a switch to error-prone DNA replication, enabling them to adapt to harsh conditions via stress-induced mutagenesis. The team concluded that their results “provide a rational framework for synthetic lethal combinations of cytostatic agents with genotoxic therapies. Such combinations could potentially generate a lethal mutational load during the initial phase of adaptive evolution, thereby reducing therapeutic failure.” They reported their findings in the June 5, 2020, issue of Science.

Nanomotoring in bladder cancer

Bladder cancer might not be the darling of cancer research at the U.S. National Institutes of Health, but researchers in South Korea believe they have devised a method for ensuring that drug agents introduced by intravesical means will stay in place long enough to exert a therapeutic effect. One of the obvious issues for such methods is that bladders don’t stay empty for very long, and thus any chemotherapies, such as Bacillus Calmette Guerin, have little time to do their work. However, a biocompatible and bioavailable, enzyme-powered polymer nanomotor can sidestep this problem by penetrating the mucosal layer, where it can remain for an extended period. These urease-immobilized nanomotors became active by converting urea into carbon dioxide and ammonia, which allowed these mini-motors to penetrate to the mucosal layer, thus providing prolonged retention “even after repeated urination.” This feature of these nano-motorboats should allow them to serve as a drug delivery carrier that could “be successfully harnessed for treating a variety of bladder diseases,” the authors said. These results are reported in the June 3, 2020, issue of ACS Nano.

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