Architecture of Vanadium-Based MXene Dysregulating Tumor Redox Homeostasis for Amplified Nanozyme Catalytic/Photothermal Therapy.

Taking the significance of the special microenvironment for tumor cell survival into account, disrupting tumor redox homeostasis is highly prospective for improving therapeutic efficacy. Herein, a multifunctional 2D vanadium-based MXene nanoplatform, V4 C3 /atovaquone@bovine albumin (V4 C3 /ATO@BSA, abbreviated as VAB) has been elaborately constructed for ATO-enhanced nanozyme catalytic/photothermal therapy. The redox homeostasis within the tumor cells is eventually disrupted, showing a remarkable anti-tumor effect. The VAB nanoplatform with mixed vanadium valence states can induce a cascade of catalyzed reactions in the tumor microenvironment, generating plenty of reactive oxygen species (ROS) with effective glutathione consumption to amplify oxidative stress. Meanwhile, the stable and strong photothermal effect of VAB under near-infrared irradiation not only causes the necrosis of tumor cells, but also improves its peroxidase-like activity. In addition, the release of ATO can effectively alleviate endogenous oxygen consumption to limit triphosadenine formation and inhibit mitochondrial respiration. As a result, the expression of heat shock proteins is effectively suppressed to overcome thermoresistance and the production of ROS can be further promoted due to mitochondrial injury. Moreover, VAB also presents high photoacoustic and photothermal imaging performances. In brief, the multifunctional nanoplatform can provide ATO-enhanced nanozyme catalytic/photothermal therapy with broadening the biomedical applications of vanadium-based MXene.

Mitochondrial respiration inhibitor enhances the anti-tumor effect of high-dose ascorbic acid in castration-resistant prostate cancer.

Previous evidences have demonstrated that anti-tumor effect of high-dose ascorbic acid is associated with the generation of reactive oxygen species (ROS) via autoxidation. Hypoxia induces therapy resistance in castration-resistant prostate cancer. As a mitochondrial respiration inhibitor, metformin has the potential to improve tumor oxygenation. In this study, we evaluate the anti-tumor effect of ascorbic acid combined with metformin in prostate cancer. We demonstrated that ascorbic acid inhibits prostate cancer cells proliferation by generating ROS, and metformin enhances the anti-tumor effects of ascorbic acid. Mechanistically, metformin reduces oxygen consumption rate and NADP+/NADPH value in prostate cancer cells, thereby increases the ROS content induced by ascorbic acid. In addition, our data demonstrated that ascorbic acid inhibits p-AKT signaling in a ROS-dependent pathway, leading to inhibition of p-mTOR expression. And metformin inhibits the p-mTOR expression by activating the AMPK signaling pathway, exerting a synergistic effect on tumor suppression with ascorbic acid. Furthermore, metformin improves tumor oxygenation, and the combined treatment effect of ascorbic acid and metformin were demonstrated in a xenograft model of prostate cancer. Taken together, our data demonstrate that metformin enhances the anti-tumor proliferation effect of ascorbic acid by increasing ROS content in castration-resistant prostate cancer. This provides a new strategy for the clinical application of high-dose ascorbic acid as an anti-tumor drug. KEY MESSAGES: Ascorbic acid inhibits tumor growth by inducing ROS generation. As a mitochondrial respiration inhibitor, metformin inhibits cellular oxygen consumption rate to improve oxygenation of prostate cancer. Metformin enhances anti-tumor effect of ascorbic acid by increasing ROS content. Ascorbic acid inhibits the mTOR expression via PI3K-AKT pathway, and metformin inhibits the mTOR expression by inhibiting AMPK signaling in prostate cancer cells.

Mitochondria: 3-bromopyruvate vs. mitochondria? A small molecule that attacks tumors by targeting their bioenergetic diversity.

Enhanced glycolysis, the classic bioenergetic phenotype of cancer cells was described by Otto Warburg approximately 90 years ago. However, the Warburg hypothesis does not necessarily imply mitochondrial dysfunction. The alkyl-halogen, 3-bromopyruvate (3BP), would not be expected to have selective targets for cancer therapy due to its high potential reactivity toward many SH side groups. Contrary to predictions, 3BP interferes with glycolysis and oxidative phosphorylation in cancer cells without side effects in normal tissues. The mitochondrial hexokinase II has been claimed as the main target. This "Organelle in focus" article presents a historical view of the use of 3BP in biochemistry and its effects on ATP-producing pathways of cancer cells. I will discuss how the alkylated enzymes contribute to the cooperative collapse of mitochondria and apoptosis. Perspectives for targeting 3BP to bioenergetics enzymes for cancer treatment will be considered.

Plant growth inhibitory activity of N, N´-di-(4-R-phenyl)-alkanediamides / Actividad inhibitoria de crecimiento de plantas de N, N’-di-(4-R-phenyl)-alcanodiamidas

Diamides are a class of metabolites that occurring in some Meliaceae plants, in Aglaia spp for example, with an ample body of biological activities, being insecticidal and herbicidal two of the most important. In our program of search for botanical pesticides, a series of N,N´-di-(4-R-phenyl)-alkanediamides was evaluated for its herbicidal activity. Many of the analogues tested exhibited moderate to good herbicidal activity both pre-emergence and post-emergence and have been found to inhibit energetic metabolism of pre-emergence weeds. The structure-activity relationships were probed by substitution on the benzene ring. Among the variations investigated, it was found that maximal herbicidal activity was obtained by substitution of –F, -CN and -Br at the aromatic portion and by n=2 of the aliphatic long chain. This last number of carbons (n=2) substitution was the key for the inhibitory activity.

Diamidas son una clase de metabolitos que estan presentes en plantas perteneciente a la familia de la Meliaceas, en Aglaia por ejemplo, poseen un amplio cuerpo de actividades biologicas, siendo la insecticida y la herbicida dos de las mas importantes. En nuestro programa para la busqueda de pesticidas botanicos, una serie de N,N’-di-(4-R-phenyl)-alkanodiamidas se evaluo para su actividad herbicida. Muchos de los analogos exhibieron desde buenas a moderadas actividades, tanto como pre-emergentes como post-emergentes y ademas se encontro que inhiben el metabolismo pre-emergente energetico de malezas. La relacion estructura-actividad fue probada por sustitución sobre al anillo aromatico. Entre las variaciones investigadas, se encontro que la maxima actividad herbicida se obtuvo por sustitución de F, CN y Br en la porcion aromatica y por n=2 del largo de la cadena alifatica. Este ultimo numero de carbonos de sustitución (n=2) fue clave para la actividad inhibitoria.