Depletion of Serotonin and Selective Inhibition of 2B Receptor Suppressed Tumor Angiogenesis by Inhibiting Endothelial Nitric Oxide Synthase and Extracellular Signal-Regulated Kinase 1/2 Phosphorylation12

The effects of serotonin (5-HT) on tumor growth are inconsistent. We investigated whether a decreased level of 5-HT affected tumor growth using 5-HT transporter knockout (5-HTT-/-) mice, which showed 5-HT depletion. When cancer cells were injected subcutaneously into both 5-HTT-/- and 5-HTT+/+ mice, the tumor growth was markedly attenuated in 5-HTT-/- mice. Serotonin levels in the blood, forebrain, and tumors of 5-HTT-/- mice bearing tumors were significantly smaller than those of their 5-HTT+/+ littermates. However, 5-HT did not increase cancer cells' proliferation in vitro. When we applied 5-HTT inhibitors to the wild mice bearing tumors, they did not inhibit tumor growth. The endothelial nitric oxide synthase (eNOS) expressions in tumors were reduced in 5-HTT-/- mice compared with 5-HTT+/+ mice. Stimulations with 5-HT (1–50 µM) induced eNOS expressions in human umbilical vein endothelial cell (HUVEC) in a concentration-dependent manner. When we measured activations of multiple signaling pathways by using a high-throughput phosphospecific antibodies platform, 5-HT stimulated the extracellular signal-regulated kinase 1/2 (ERK1/2) in HUVEC. Moreover, we found that the physiological level of 5-HT induced phosphorylation of both ERK1/2 and eNOS in HUVEC. Human umbilical vein endothelial cell expressed both 5-HT2B and 5-HT2C receptors. SB204741, a specific 5-HT2B receptor inhibitor, blocked 5-HT-induced ERK1/2 and eNOS phosphorylations, whereas RS102221, a specific 5-HT2C receptor inhibitor, did not in HUVEC. SB204741 reduced microvessel density in tumors and inhibited the proliferation of HUVEC in vitro. These results suggest that regulation of 5-HT and 5-HT receptors, especially the 5-HT2B receptor, may serve as a therapeutic strategy in cancer therapy

Efficacy of paclitaxel‐carboplatin with bevacizumab as a late‐line therapy for patients with advanced nonsquamous non‐small cell lung cancer: A platinum rechallenge

Abstract Background There is no well‐established late‐line treatment for advanced nonsquamous non‐small cell lung cancer (NSCLC). Therefore, we retrospectively determined the efficacy and safety of platinum rechallenge with paclitaxel‐carboplatin and bevacizumab in patients with nonsquamous NSCLC as a late‐line therapy in a clinical setting. Methods Thirty patients with nonsquamous NSCLC who received paclitaxel‐carboplatin with bevacizumab therapy as a late‐line treatment at Sendai Kousei Hospital (Miyagi, Japan) between December 2011 and December 2021 were enrolled into the study. The efficacy and safety of this treatment were evaluated. The patients were further categorized into responders and nonresponders, and predictive factors of treatment response were estimated. Results The median progression‐free survival (PFS) was 6.3 (range, 4.9–6.8) months, and the median overall survival (OS) was 11.8 (range, 7.2–17.2) months. There were no significant differences in PFS and OS between patients with and those without epidermal growth factor receptor mutations. In the univariate analyses of this study, responders were younger than nonresponders (p = 0.012). No fatal adverse events were reported. Conclusions With the increase in the number of treatment options in recent years, the sequence of treatments and overall therapeutic strategy are becoming increasingly important. Thus, platinum rechallenge with paclitaxel‐carboplatin and bevacizumab, a late‐line treatment for patients with nonsquamous NSCLC, may be an effective therapeutic option