Dual inhibition of oxidative phosphorylation and glycolysis to enhance cancer therapy.

Dual suppression of oxidative phosphorylation (OXPHOS) and glycolysis can disrupt metabolic adaption of cancer cells, inhibiting energy supply and leading to successful cancer therapy. Herein, we have developed an α-tocopheryl succinate (α-TOS)-functionalized iridium(III) complex Ir2, a highly lipophilic mitochondria targeting anticancer molecule, could inhibit both oxidative phosphorylation (OXPHOS) and glycolysis, resulting in the energy blockage and cancer growth suppression. Mechanistic studies reveal that complex Ir2 induces reactive oxygen species (ROS) elevation and mitochondrial depolarization, and triggers DNA oxidative damage. These damages could evoke the cancer cell death with the mitochondrial-relevant apoptosis and autophagy. 3D tumor spheroids experiment demonstrates that Ir2 owned superior antiproliferation performance, as the potent anticancer agent in vivo. This study not only provided a new path for dual inhibition of both mitochondrial OXPHOS and glycolytic metabolisms with a novel α-TOS-functionalized metallodrug, but also further demonstrated that the mitochondrial-relevant therapy could be effective in enhancing the anticancer performance.

Mitochondria-targeted ruthenium complexes can be generated in vitro and in living cells to target triple-negative breast cancer cells by autophagy inhibition.

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer, which owned severe resistance to platinum-based anticancer agents. Herein, we report a new metal-arene complex, Ru-TPE-PPh3, which can be synthesized in vitro and in living cells with copper catalyzed the cycloaddition reaction of Ru-azide and alkynyl (CuAAC). The complex Ru-TPE-PPh3 exhibited superior inhibition of the proliferation of TNBC MDA-MB-231 cells with an IC50 value of 4.0 µM. Ru-TPE-PPh3 could induce the over production of reactive oxygen species (ROS) to initiate the oxidative stress, and further damage the mitochondria both functionally and morphologically, as loss of mitochondrial membrane potential (MMP) and cutting the supply of adenosine triphosphate (ATP), the disappearance of cristae structure. Moreover, the damaged mitochondria evoked the occurrence of mitophagy with the autophagic flux blockage and cell death. The complex Ru-TPE-PPh3 also demonstrated excellent anti-proliferative activity in 3D MDA-MB-231 multicellular tumor spheroids (MCTSs), indicating the potential to inhibit solid tumors in living cells. This study not only provided a potent agent for the TNBC treatment, but also demonstrated the universality of the bioorthogonally catalyzed lethality (BCL) strategy through CuAAC reation.

Mitochondria-targeted Pt(IV) prodrugs conjugated with an aggregation-induced emission luminogen against breast cancer cells by dual modulation of apoptosis and autophagy inhibition.

Theranostic anticancer agents with dual functions of diagnosis and therapy are in highly demand for breast cancer. Herein, a triphenylphosphonium (TPP)-decorated aggregation-induced emission (AIE)-based Pt(IV) prodrug ACPt was developed, which exhibited superior anticancer performance with novel anticancer mechanism of dual modulation of apoptosis and autophagy inhibition. The experimental data showed that ACPt induced increased reactive oxygen species (ROS), and decreased mitochondrial membrane potential (MMP). The morphology and function of mitochondria were also severely damaged and ACPt showed strong inhibition to both mitochondrial and glycolytic bioenergetics. Moreover, DNA damage and cell cycle arrest in the S-phase were also observed after the ACPt treatment, eventually leading to the apoptosis and autophagy inhibition of cancer cells. Furthermore, ACPt also indicated excellent anti-proliferation activity in 3D multicellular tumor spheroids (MCTSs), suggesting the potential to inhibit solid tumors in vivo. Our observation demonstrated that ACPt could serve as a promising anticancer theranostic agent toward breast cancers for prodrug activation monitoring and image-guided chemotherapy.

Fighting metallodrug resistance through alteration of drug metabolism and blockage of autophagic flux by mitochondria-targeting AIEgens.

Metallodrug resistance has attracted a great deal of attention in cancer treatment. According to the cisplatin (cis-Pt) anticancer mechanism, a new strategy to overcome cis-Pt resistance through mitochondrial dysfunction is proposed. Two mitochondria-targeted aggregation-induced emission fluorogens (AIEgens) were first synthesized, named DP-PPh3 and TPE-PPh3, which showed superior capacities to overcome the cis-Pt resistance of lung cancer cells (A549R) by the alteration of drug metabolism (up-regulation of influx CTR1 and down-regulation of efflux MRP2) and blockage of autophagic flux (failure of the degradation of autophagosomes). This study is the first time that AIEgens are utilized in the treatment of cis-Pt resistant cancer cells. Moreover, the underlying molecular mechanism was fully revealed. Triphenylphosphonium (PPh3)-decorated AIEgens DP-PPh3 and TPE-PPh3 not only successfully realized aggregation and the imaging of mitochondria in A549R cells, but also activated cytotoxicity towards A549R cells. DP-PPh3 and TPE-PPh3 could induce ROS production, disrupt the mitochondrial structure, and impair mitochondrial and glycolytic metabolism. Furthermore, the anticancer efficacy of these drugs was demonstrated in 3D multicellular tumor spheroids (MCTSs) of A549R cells in vitro and in tumor-bearing nude mice in vivo. This AIE-PPh3 strategy not only promoted cytotoxicity towards cancer cells but also provided a new pathway for the treatment of metallodrug resistance.

Pediatric Clinical Trials in Mainland China Over the Past Decade (From 2009 to 2020).

In mainland China, there remains a shortage of pediatric drugs. The Chinese government has recently launched policies and incentives to encourage pediatric drug development and clinical trials. However, data on the characteristics or development trends of these trials are limited. In this review, we extracted source data from the Chinese Clinical Trials Registry and Information Transparency Platform and systematically reviewed the pediatric clinical trials conducted in mainland China from 2009 to 2020, a comprehensive process evaluation of the pediatric drug clinical trials development in the past decade, providing data support to policy makers and industry stakeholders. We included 487 pediatric clinical trials. Over the past decade, the number of pediatric trials has increased, especially since 2016. The most common therapeutic areas were infectious diseases (n = 108, 22.2%), agents for preventive purpose (n = 99, 20.3%), and neurological and psychiatric diseases (n = 71, 14.6%). The number of clinical trials involving epilepsy (39, 10.1%), asthma (33, 8.5%), and influenza (24, 6.2%) were the highest. The distribution of leading institutions is unbalanced in mainland China, with most units in East China (34.0%) and few in Southwest China (6.9%). China has made progress in improving the research and development environment of pediatric drugs and increasing pediatric trials. However, a wide gap in pediatric drug development and clinical trials quality exists between China and the developed countries. The pharmaceutical industry in China has faced grim setbacks, including study duplication, lack of innovation, poor research design, and unbalanced resource allocation. Thus, we suggest that the Chinese government should adjust their policies to improve innovation and clinical design capacity, and optimize resource allocation between regions.