Inhibition of Murine Breast Cancer Metastases by Hydrophilic As4S4 Nanoparticles Is Associated With Decreased ROS and HIF-1α Downregulation

Arsenic sulfide (As4S4) is a mineral drug that can be administrated orally and has been applied in the treatment of myeloid leukemia. The aim of this work is to investigate the therapeutic effect of As4S4 in highly metastatic triple-negative breast cancer (TNBC) animal model, as As4S4 has not been applied in the treatment of breast cancer yet. To overcome the poor solubility of original As4S4, a formulation of hydrophilic As4S4 nanoparticles (e-As4S4) developed previously was applied to mouse breast cancer cells as well as the tumor-bearing mice. It was shown that e-As4S4 was much more cytotoxic than r-As4S4, strongly inhibiting the proliferation of the cells and scavenging intracellular reactive oxygen species (ROS). The oral administration of e-As4S4 significantly increased the accumulation of arsenic in the tumor tissue and eliminated ROS in tumor tissues. Besides, e-As4S4 could also inhibit the activation of hypoxia-inducible factor-1α (HIF-1α) and NLRP3 inflammasomes. Consequently, the angiogenesis was reduced, the metastasis to lung and liver was inhibited and the survival of tumor-bearing mice was prolonged. In conclusion, e-As4S4 holds great potential for an alternative therapeutics in the treatment of breast cancer, due to its unique function of correcting the aggressive microenvironment

CDK4/6 inhibition suppresses p73 phosphorylation and activates DR5 to potentiate chemotherapy and immune checkpoint blockade

Targeting cyclin-dependent kinases 4 and 6 (CDK4/6) is a successful therapeutic approach against breast and other solid tumors. Inhibition of CDK4/6 halts cell cycle progression and promotes antitumor immunity. However, the mechanisms underlying the antitumor activity of CDK4/6 inhibitors are not fully understood. We found that CDK4/6 bind and phosphorylate the p53 family member p73 at threonine 86, which sequesters p73 in the cytoplasm. Inhibition of CDK4/6 led to dephosphorylation and nuclear translocation of p73, which transcriptionally activated death receptor 5 (DR5), a cytokine receptor and key component of the extrinsic apoptotic pathway. p73-mediated induction of DR5 by CDK4/6 inhibitors promoted immunogenic cell death of cancer cells. Deletion of DR5 in cancer cells in vitro and in vivo abrogated the potentiating effects of CDK4/6 inhibitors on immune cytokine TRAIL, 5-fluorouracil chemotherapy, and anti–PD-1 immunotherapy. Together, these results reveal a previously unrecognized consequence of CDK4/6 inhibition, which may be critical for potentiating the killing and immunogenic effects on cancer cells.Fil: Tong, Jingshan. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Tan, Xiao. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Song, Xiangping. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Gao, Man. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Risnik, Denise Mariel. Univeristy of Pittsburgh. School of Medicine; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Hao, Suisui. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Ermine, Kaylee. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Wang, Peng. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Li, Hua. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Huang, Yi. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Yu, Jian. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Zhang, Lin. Univeristy of Pittsburgh. School of Medicine; Estados Unido

Integration of a Superparamagnetic Scaffold and Magnetic Field To Enhance the Wound-Healing Phenotype of Fibroblasts

Most of the existing scaffolds for guiding tissue regeneration do not provide direct mechanical stimulation to the cells grown on them. In this work, we used nanofibrous superparamagnetic scaffolds with applied magnetic fields to build a “dynamic” scaffold platform and investigated the modulating effects of this platform on the phenotypes of fibroblasts. The results of enzyme-linked immunosorbent and transwell assays indicated that fibroblasts cultivated in this platform secreted significantly higher type I collagen, vascular endothelial growth factor A, and transforming growth factor-β1 and did so in a time-dependent manner. At the same time, they produced fewer pro-inflammatory cytokines, including interleukin-1β and monocyte chemoattractant protein-1; this, in turn, accelerated the osteogenesis of preosteoblasts with the help of increased basic fibroblast growth factor as well as balanced extracellular matrix components. Mechanistic studies revealed that the platform modulated the phenotypic polarization of fibroblasts through the activation of components of integrin, focal adhesion kinase, and extracellular signal-regulated kinase signaling pathways and the inhibition of the activation of Toll-like receptor-4 and nuclear factor κB. Overall, the platform promoted the wound-healing phenotype of fibroblasts, which would be of great benefit to the scaffold-guided tissue regeneration