Developing a Mathematical Model of Intracellular Calcium Dynamics for Evaluating Combined Anticancer Effects of Afatinib and RP4010 in Esophageal Cancer.

Targeting dysregulated Ca2+ signaling in cancer cells is an emerging chemotherapy approach. We previously reported that store-operated Ca2+ entry (SOCE) blockers, such as RP4010, are promising antitumor drugs for esophageal cancer. As a tyrosine kinase inhibitor (TKI), afatinib received FDA approval to be used in targeted therapy for patients with EGFR mutation-positive cancers. While preclinical studies and clinical trials have shown that afatinib has benefits for esophageal cancer patients, it is not known whether a combination of afatinib and RP4010 could achieve better anticancer effects. Since TKI can alter intracellular Ca2+ dynamics through EGFR/phospholipase C-γ pathway, in this study, we evaluated the inhibitory effect of afatinib and RP4010 on intracellular Ca2+ oscillations in KYSE-150, a human esophageal squamous cell carcinoma cell line, using both experimental and mathematical simulations. Our mathematical simulation of Ca2+ oscillations could fit well with experimental data responding to afatinib or RP4010, both separately or in combination. Guided by simulation, we were able to identify a proper ratio of afatinib and RP4010 for combined treatment, and such a combination presented synergistic anticancer-effect evidence by experimental measurement of intracellular Ca2+ and cell proliferation. This intracellular Ca2+ dynamic-based mathematical simulation approach could be useful for a rapid and cost-effective evaluation of combined targeting therapy drugs.

Ionic silicon improves endothelial cells' survival under toxic oxidative stress by overexpressing angiogenic markers and antioxidant enzymes.

Oxidative stress, induced by harmful levels of reactive oxygen species, is a common occurrence that impairs proper bone defect vascular healing through the impairment of endothelial cell function. Ionic silicon released from silica-based biomaterials, can upregulate hypoxia-inducible factor-1α (HIF-1α). Yet it is unclear whether ionic Si can restore endothelial cell function under oxidative stress conditions. Therefore, we hypothesized that ionic silicon can help improve human umbilical vein endothelial cells' (HUVECs') survival under toxic oxidative stress. In this study, we evaluated the ionic jsilicon effect on HUVECs viability, proliferation, migration, gene expression, and capillary tube formation under normal conditions and under harmful hydrogen peroxide levels. We demonstrated that 0.5-mM Si4+ significantly enhanced angiogenesis in HUVECs under normal condition (p < 0.05). HUVECs exposed to 0.5-mM Si4+ presented a morphological change, even without the bed of Matrigel, and formed significantly more tube-like structures than the control (p < 0.001). In addition, 0.5-mM Si4+ enhanced cell viability in HUVECs under harmful H2 O2 levels. HIF-1α, vascular endothelial growth factor-A, and vascular endothelial growth factor receptor-2 were overexpressed more than twofold in silicon-treated HUVECs, under normal and toxic H2 O2 conditions. Moreover, the HUVECs were treated with 0.5-mM Si4+ overexpressed superoxide dismutase-1 (SOD-1), catalase-1 (Cat-1), and nitric oxide synthase-3 (NOS3) under normal and oxidative stress environment (p < 0.01). A computational model was used for explaining the antioxidant effect of Si4+ in endothelial cells and human periosteum cells by SOD-1 enhancement. In conclusion, we demonstrated that 0.5-mM Si4+ can recover the HUVECs' viability under oxidative stress conditions by reducing cell death and upregulating expression of angiogenic and antioxidant factors.