Background/Aim: For immune checkpoint inhibitor (ICI)-pretreated patients, docetaxel and ramucirumab (DOC+RAM) combination therapy may be more effective compared to patients not receiving ICI treatment. Patients and Methods: From June 2013 to July 2018, 39 patients with advanced/recurrent non-small cell lung cancer underwent DOC+RAM therapy. We analyzed the efficacy and safety of DOC+RAM therapy based on the presence (pre-ICI+) or absence (pre-ICI-) of ICI pretreatment history. Results: Of the 39 patients treated with DOC+RAM, we identified 18 (46%) pre-ICI+ patients. Overall response rates for DOC+RAM concerning pre-ICI+ and pre-ICI-patients were 38.9% vs. 19.0%, respectively. Median progression-free survival (PFS) was 5.7 vs. 2.3 months [hazard ratio(HR)=0.36; 95% confidence interval (CI)=0.16-0.80]. Adverse events such as fever, myalgia, arthritis, pleural effusion, and pneumonitis tended to be increased in pre-ICI+ patients. Conclusion: Despite increased toxicity concerns, DOC+RAM therapy in pre-ICI+ patients showed a trend for tumor regression improvement and statistically significant prolongation of PFS. Lung cancer is one of the leading causes of mortality worldwide. Immune checkpoint inhibitor (ICI) monotherapy or combination chemotherapy with cytotoxic agents has been developed for patients with advanced non-small cell lung cancer (NSCLC). However, median progression-free survival (PFS) is limited (1, 2). Applying more effective sequential chemotherapy is important for the prolongation of life. Recently, salvage cytotoxic chemotherapy after ICI treatment has been reported to increase antitumor effects (3-6). Moreover, it has been suggested that the efficacy of sequential cytotoxic chemotherapy may improve both the overall response rate (ORR) and PFS, regardless of the efficacy of previous ICI treatment and programmed death-ligand 1 (PD-L1) expression (4). Some studies have reported that activation of the vascular endothelial growth factor (VEGF) and its receptor (VEGFR) inhibitory (VEGF/VEGFR) signal is one of the ICI resistant mechanisms, and that combination therapy of a VEGF/VEGFR inhibitor with ICI had a synergistic and improved antitumor effect (7). It has also been reported that using docetaxel with ramucirumab, a VEGFR inhibitor combination therapy (DOC+RAM) for ICI-treated patients may be more effective than for patients in historical case controls (6). Therefore, we conducted a retrospective comparative study on the efficacy and toxicity of DOC+RAM therapy at our hospital.
Arginine-rich, cell-penetrating peptides (e.g., Tat-peptide, penetratin, and polyarginine) are used to carry therapeutic molecules such as oligonucleotides, DNA, peptides, and proteins across cell membranes. Two types of processes are being considered to cross the cell membranes: one is an endocytic pathway, and another is an energy-independent, nonendocytic pathway. However, the latter is still not known in detail. Here, we studied the effects of the chain length of polyarginine on its interaction with an anionic phospholipid large unilamellar vesicle (LUV) or a giant vesicle using poly-l-arginine composed of 69 (PLA69), 293 (PLA293), or 554 (PLA554) arginine residues, together with octaarginine (R8). ζ-potential measurements confirmed that polyarginine binds to LUV via electrostatic interactions. Circular dichroism analysis demonstrated that the transition from the random coil to the α-helix structure upon binding to LUV occurred for PLA293 and PLA554, whereas no structural change was observed for PLA69 and R8. Fluorescence studies using membrane probes revealed that the binding of polyarginine to LUV affects the hydration and packing of the membrane interface region, in which the degree of membrane insertion is greater for the longer polyarginine. Isothermal titration calorimetry measurements demonstrated that although the binding affinity (i.e., the Gibbs free energy of binding) per arginine residue is similar among all polyarginines the contribution of enthalpy to the energetics of binding of polyarginine increases with increasing polymer chain length. In addition, confocal laser scanning microscopy showed that all polyarginines penetrate across giant vesicle membranes, and the order of the amount of membrane penetration is R8 ≈ PLA69 < PLA293 ≈ PLA554. These results suggest that the formation of α-helical structure upon lipid binding drives the insertion of polyarginine into the membrane interior, which appears to enhance the membrane penetration of polyarginine.
Apolipoprotein A-I (apoA-I) accepts cholesterol and phospholipids from ATP-binding cassette transporter Al (ABCA1)-expressing cells to form high-density lipoprotein (HDL). Human apoA-I has two tertiary structural domains and the C-terminal domain (approximately amino acids 190–243) plays a key role in lipid binding. Although the high lipid affinity region of the C-terminal domain of apoA-I (residues 223–243) is essential for the HDL formation, the function of low lipid affinity region (residues 191–220) remains unclear. To evaluate the role of residues 191–220, we analyzed the structure, lipid binding properties, and HDL formation activity of Δ191–220 apoA-I, in comparison to wild-type and Δ223–243 apoA-I. Although deletion of residues 191–220 has a slight effect on the tertiary structure of apoA-I, the Δl91–220 variant showed intermediate behavior between wild-type and Δ223–243 regarding the formation of hydrophobic sites and lipid interaction through the C-terminal domain. Physicochemical analysis demonstrated that defective lipid binding of Δl91–220 apoA-I is due to the decreased ability to form α-helix structure which provides the energetic source for lipid binding. In addition, the ability to form HDL particles in vitro and induce cholesterol efflux from ABC Al-expressing cells of Δ191–220 apoA-I was also intermediate between wild-type and Δ223–243 apoA-I. These results suggest that despite possessing low lipid affinity, residues 191–220 play a role in enhancing the ability of apoA-I to bind to and solubilize lipids by forming α-helix upon lipid interaction. Our results demonstrate that the combination of low lipid affinity region and high lipid affinity region of apoA-I is required for efficient ABCA1-dependent HDL formation.
As the principal component of high-density lipoprotein (HDL), apolipoprotein (apo) A-I plays essential roles in lipid transport and metabolism. Because of its intrinsic conformational plasticity and flexibility, the molecular details of the tertiary structure of lipid-free apoA-I have not been fully elucidated. Previously, we demonstrated that the stability of the N-terminal helix bundle structure is modulated by proline substitution at the most hydrophobic region (residues around Y18) in the N-terminal domain. Here we examine the effect of proline substitution at S55 located in another relatively hydrophobic region compared to most of the helix bundle domain to elucidate the influences on the helix bundle structure and lipid interaction. Fluorescence measurements revealed that the S55P mutation had a modest effect on the stability of the bundle structure, indicating that residues around S55 are not pivotally involved in the helix bundle formation, in contrast to the insertion of proline at position 18. Although truncation of the C-terminal domain (Δ190-243) diminishes the lipid binding of apoA-I molecule, the mutation S55P in addition to the C-terminal truncation (S55P/Δ190-243) restored the lipid binding, suggesting that the S55P mutation causes a partial unfolding of the helix bundle to facilitate lipid binding. Furthermore, additional proline substitution at Y18 (Y18P/S55P/Δ190-243), which leads to a drastic unfolding of the helix bundle structure, yielded a greater lipid binding ability. Thus, proline substitutions in the N-terminal domain of apoA-I that destabilized the helix bundle promoted lipid solubilization. These results suggest that not only the hydrophobic C-terminal helical domain but also the stability of the N-terminal helix bundle in apoA-I are important modulators of the spontaneous solubilization of membrane lipids by apoA-I, a process that leads to the generation of nascent HDL particles.Keywords amphipathic α-helix; apolipoprotein A-I; helix bundle structure; lipid binding; proline substitution
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