The epidermal growth factor receptor（EGFR）—tyrosine kinase inhibitors（TKIs） monotherapies have limited efficacy in the treatment of EGFR mutation-negative non-small cell lung cancers（NSCLCs）. In the present study, we aimed to investigate the combined effect of erlotinib（ER） and cabozantinib（CAB） on NSCLC cell lines harboring wild-type EGFR and to optimize the dosage regimens using pharmacodynamic（PD） modeling and simulation. Therefore, we examined the combined effect of ER and CAB on cell viability, cloning, apoptosis induction, migration and growth dynamics in H1299 and A549 cells. PD modeling and simulation were also performed to quantitatively describe the H1299 cells growth dynamics and to optimize the dosage regimens as well. Our results showed that CAB effectively enhanced the sensitivity of both cell lines to ER. The PD models fitted the data well, and some important parameters were obtained. The exponential（λ_0） and linear（λ_1） growth rates of H1299 cells were 0.0241 h^（–1） and 360 cells？h^（–1）, respectively. The Emax of ER and CAB was 0.0091 h^（–1） and 0.0085 h^（–1）, and the EC50 was 0.812 μM and 1.16 μM, respectively. The synergistic effect observed in the experiments was further confirmed by the estimated combination index φ（1.37）,（95% confidence interval： 1.24–1.50）, obtained from PD modeling. Furthermore, the dosage regimens were optimized using simulations. In summary, both the experimental and modeling results demonstrated the synergistic interaction between ER and CAB in NSCLCs without EGFR mutations. Sequential combinations of ER and CAB provided an option for the therapy of the NSCLCs with wild-type EGFR, which would provide some references for preclinical study and translational research as well.
Sulfotransferases（SULTs） are one of the most important phase II drug-metabolizing enzymes. Among them, aryl sulfotransferases（SULT1A1） and estrogen sulfotransferase（EST, SULT1E1） belong to the rSULT1 family that catalyzes sulfation of phenolic compounds. Dopamine（DA） acts as a vital neurotransmitter in central nervous system（CNS） and regulates a variety of activities in periphery. In our study, we aim to detect the effects of exogenous DA and levodopa（L-DOPA） on rSULTs（rSULT1A1 and rSULT1E1） in rat liver. In order to achieve this target, varying doses of DA（0, 2, 10 and 100 mg/kg/d） and L-DOPA（0, 5, 25 and 125 mg/kg/d） were provided to male and female rats, respectively. Real-time PCR assay and western blot were used in the determination of the mRNA and protein expression of rSULTs. PNPS assay and radioactivity assay were applied to the detection of enzyme activity of rSULT1A1 and rSULT1E1, respectively. Our results showed that DA induced the expression and activity of rSULT1A1 in the liver of male and female rats and DA had little effect on rSULT1E1. However, L-DOPA caused no evident change of rSULT1A1 in both sex and had no significant effect on rSULT1E1 in female rat liver, but increased rSULT1E1 expression and activity only in male rat liver when administered at high dose. Our results suggest that DA plays different roles in the regulation of rSULT1A1 and rSULT1E1 when it is in periphery or in the CNS.
