Cancer cells usually adapt metabolic phenotypes to chemotherapeutics.Adefensive strategy against this flexibility is to modulate signaling pathwaysr elevant to cancer bioenergetics.Atriphenylphosphonium-modified terpyridine platinum(II) complex (TTP) was designed to inhibit thioredoxin reductase (TrxR) and multiple metabolisms of cancer cells. TTP exhibited enhanced cytotoxicity against cisplatin-insensitive human ovarian cancer cells in ac aspase-3-independent manner and showed preferential inhibition to mitochondrial TrxR. The morphology and function of mitochondria were severely damaged, and the levels of mitochondrial and cellular reactive oxygen species were decreased. As ar esult, TTP exerted strong inhibition to both mitochondrial and glycolytic bioenergetics,t hus inducing cancer cells to enter ah ypometabolic state.

A cationic copper complex with triphenylphosphine as a targeting group preferentially accumulates in mitochondria of tumor cells and strongly inhibits their proliferation.

Phenanthriplatin, a monofunctional anticancer agent derived from cisplatin, shows significantly enhanced DNA covalent binding activity compared to its parent complex. To understand the underlying molecular mechanism, we use single molecule studies with optical tweezers to probe the kinetics of DNA-phenanthriplatin binding as well as DNA binding to several control complexes. The time-dependent extension of single λ-DNA molecules were monitored at constant applied forces and compound concentrations, followed by rinsing with a compound-free solution. DNA-phenanthriplatin association consisted of fast and reversible DNA lengthening with time constant τ ~10 s, followed by slow and irreversible DNA elongation that reaches equilibrium in ~30 min. In contrast, only reversible fast DNA elongation occurs for its stereoisomer trans-phenanthriplatin, suggesting that the distinct two-rate kinetics of phenanthriplatin is sensitive to the geometric conformation of the complex. Furthermore, no DNA unwinding is observed for pyriplatin, in which the phenanthridine ligand of phenanthriplatin is replaced by the smaller pyridine molecule, indicating that the size of the aromatic group is responsible for the rapid DNA elongation. These findings suggest that the mechanism of binding of phenanthriplatin to DNA involves rapid, partial intercalation of the phenanthridine ring followed by slower substitution of the adjacent chloride ligand by, most likely, the N7 atom of a purine base. The cis isomer affords the proper stereochemistry at the metal center to facilitate essentially irreversible DNA covalent binding, a geometric advantage not afforded by trans phenanthriplatin. This study demonstrates that reversible DNA intercalation can be employed to provide a robust transition state that is efficiently converted to an irreversible DNA-Pt bound state.

Aneuploidy, defined as whole chromosome gains and losses, is associated with poor patient prognosis in many cancer types. However, the condition causes cellular stress and cell cycle delays, foremost in G1 and S phase. Here, we investigate how aneuploidy causes both slow proliferation and poor disease outcome. We test the hypothesis that aneuploidy brings about resistance to chemotherapies because of a general feature of the aneuploid condition—G1 delays. We show that single chromosome gains lead to increased resistance to the frontline chemotherapeutics cisplatin and paclitaxel. Furthermore, G1 cell cycle delays are sufficient to increase chemotherapeutic resistance in euploid cells. Mechanistically, G1 delays increase drug resistance to cisplatin and paclitaxel by reducing their ability to damage DNA and microtubules, respectively. Finally, we show that our findings are clinically relevant. Aneuploidy correlates with slowed proliferation and drug resistance in the Cancer Cell Line Encyclopedia (CCLE) dataset. We conclude that a general and seemingly detrimental effect of aneuploidy, slowed proliferation, provides a selective benefit to cancer cells during chemotherapy treatment.

A trans-DDP based monofunctional phenanthridine Pt(ii) complex was synthesized and characterized. Its anticancer activity was studied in vitro on a panel of human cancer cell lines and mouse intestinal cancer organoids. This complex displays significant antitumor properties, with a different spectrum of activity than that of classic bifunctional cross-linking agents like cisplatin.

Effective delivery to the brain limits the development of novel glioblastoma therapies. Here, we introduce conjugation between platinum­(IV) prodrugs of cisplatin and perfluoroaryl peptide macrocycles to increase brain uptake. We demonstrate that one such conjugate shows efficacy against glioma stem-like cells. We investigate the pharmacokinetics of this conjugate in mice and show that the amount of platinum in the brain after treatment with the conjugate is 15-fold greater than with cisplatin after 5 h.

In response to DNA damage, a synthetic lethal relationship exists between the cell cycle checkpoint kinase MK2 and the tumor suppressor p53. Here, we describe the concept of augmented synthetic lethality (ASL): depletion of a third gene product enhances a preexisting synthetic lethal combination. We show that loss of the DNA repair protein XPA markedly augments the synthetic lethality between MK2 and p53, enhancing anti-tumor responses alone and in combination with cisplatin chemotherapy. Delivery of siRNA-peptide nanoplexes co-targeting MK2 and XPA to pre-existing p53-deficient tumors in a highly aggressive, immunocompetent mouse model of lung adenocarcinoma improves long-term survival and cisplatin response beyond those of the synthetic lethal p53 mutant/MK2 combination alone. These findings establish a mechanism for co-targeting DNA damageinduced cell cycle checkpoints in combination with repair of cisplatin-DNA lesions in vivo using RNAi nanocarriers, and motivate further exploration of ASL as a generalized strategy to improve cancer treatment.

Truck automation is emerging as an innovative technology with benefits in traffic safety and the economy to revolutionize freight traffic. Despite these benefits, the potential negative or positive effects of different driving automation levels (from no automation to full automation) on highway geometry remained to be determined. In this study, differences related to sight distance characteristics among varied automation levels were firstly discussed and calibrated. Then, seven analysis scenarios of typical levels were proposed. Based on each level with tailored characteristics, the current models of geometric design elements including the required stopping sight distance, horizontal sight line offset, and lengths of vertical curves were revised. Finally, impacts of each level on computed values of those elements were evaluated. Results show that high or full driving automation could substantially lower the requirements of geometric design. Active safety systems have a similar role but with less significant effects. Differently, the driver assistance and partial or conditional automation systems put a higher demand on the road geometric design in terms of driving safety. Outcomes of this study can be used to design real-world geometry of dedicated lanes and provide a methodological basis for the operation of different driving automation features.