Norihiko Sugisawa

Intra-abdominal infectious complications following gastrectomy in patients with excessive visceral fat

BackgroundExcessive visceral fat may be a better predictor of the development of postoperative morbidity after gastrectomy than body mass index (BMI). The aim of the present study was to clarify the most appropriate fat parameter to predict pancreas-related infection and anastomotic leakage following gastrectomy.MethodsThe study was performed in 206 patients who underwent curative gastrectomy at the Shizuoka Cancer Center between April 2008 and March 2009. Relationships between fat parameters, including visceral fat area (VFA), and early surgical outcomes were investigated. The risk factors for pancreas-related infection and anastomotic leakage were identified using univariate and multivariate analyses.ResultsThere was no strong association between any of the fat parameters and operating time, intraoperative blood loss, the number of lymph nodes retrieved, or the duration of the postoperative hospital stay. Pancreas-related infection occurred in 18 patients (8.7%), whereas anastomotic leakage was observed in 10 patients (4.9%). Of all the fat parameters, only VFA was found to be an independent risk factor for both pancreas-related infection and anastomotic leakage, with odds ratios (95% confidence intervals) of 1.015 (1.005–1.025) and 1.010 (1.000–1.021), respectively.ConclusionsExcessive visceral fat, represented by the VFA, was found to be an independent risk factor for both pancreas-related infection and anastomotic leakage following gastrectomy.

Synthetic Analogs of Curcumin Modulate the Function of Multidrug Resistance–Linked ATP-Binding Cassette Transporter ABCG2

Multidrug resistance (MDR) caused by the overexpression of ATP-binding cassette (ABC) transporters in cancer cells is a major obstacle in cancer chemotherapy. Previous studies have shown that curcumin, a natural product and a dietary constituent of turmeric, inhibits the function of MDR-related ABC transporters, including ABCB1, ABCC1, and especially ABCG2. However, the limited bioavailability of curcumin prevents its use for modulation of the function of these transporters in the clinical setting. In this study, we investigated the effects of 24 synthetic curcumin analogs with increased bioavailability on the transport function of ABCG2. The screening of the 24 synthetic analogs by means of flow cytometry revealed that four of the curcumin analogs (GO-Y030, GO-Y078, GO-Y168, and GO-Y172) significantly inhibited the efflux of the ABCG2 substrates, mitoxantrone and pheophorbide A, from ABCG2-overexpressing K562/breast cancer resistance protein (BCRP) cells. Biochemical analyses showed that GO-Y030, GO-Y078, and GO-Y172 stimulated the ATPase activity of ABCG2 at nanomolar concentrations and inhibited the photolabeling of ABCG2 with iodoarylazidoprazosin, suggesting that these analogs interact with the substrate-binding sites of ABCG2. In addition, when used in cytotoxicity assays, GO-Y030 and GO-Y078 were found to improve the sensitivity of the anticancer drug, SN-38, in K562/BCRP cells. Taken together, these results suggest that nontoxic synthetic curcumin analogs with increased bioavailability, especially GO-Y030 and GO-Y078, inhibit the function of ABCG2 by directly interacting at the substrate-binding site. These synthetic curcumin analogs could therefore be developed as potent modulators to overcome ABCG2-mediated MDR in cancer cells.

Lymph nodes around the posterior gastric artery: their existence, frequency, and clinical implications

PurposeThe lymphatic flow along the posterior gastric artery (PGA) is considered of possible clinical importance in terms of lymphatic metastasis; however, little is known about the lymph nodes (LNs) around this artery. The purpose of this study was to establish if LNs exist around the PGA and to evaluate their clinical implications.MethodsWe examined the tissues surrounding the PGA from 21 cadavers to search for LNs. We also investigated the patterns of lymphatic metastases in patients who underwent surgery for gastric neoplasms at our institute to detect their presence along the PGA.ResultsThe PGA was identified in 11 cadavers, and LNs around the PGA were detected microscopically in 2 of these. Lymphatic metastasis directly to the LNs at the splenic artery without any metastases was regarded as skip metastasis along the PGA. Skip metastasis was found in two of ten patients who underwent surgery for remnant gastric cancer.ConclusionsThe existence of LNs around the PGA was confirmed, and based on our findings, lymphatic metastasis through the PGA is possible in patients with remnant gastric cancer.

A novel potent ABCB1 modulator, phenethylisoquinoline alkaloid, reverses multidrug resistance in cancer cell.

ATP-binding cassette (ABC) transporters, which are concerned with the efflux of anticancer drugs from cancer cells, have a pivotal role in multidrug resistance (MDR). In particular, ABCB1 is a well-known ABC transporter that develops MDR in many cancer cells. Some ABCB1 modulators can reverse ABCB1-mediated MDR; however, no modulators with clinical efficacy have been approved. The aim of this study was to identify novel ABCB1 modulators by using high-throughput screening. Of the 5861 compounds stored at Tohoku University, 13 compounds were selected after the primary screening via a fluorescent plate reader-based calcein acetoxymethylester (AM) efflux assay. These 13 compounds were validated in a flow cytometry-based calcein AM efflux assay. Two isoquinoline derivatives were identified as novel ABCB1 inhibitors, one of which was a phenethylisoquinoline alkaloid, (±)-7-benzyloxy-1-(3-benzyloxy-4-methoxyphenethyl)-1,2,3,4-tetrahydro-6-methoxy-2-methylisoquinoline oxalate. The compound, a phenethylisoquinoline alkaloid, was subsequently evaluated in the cytotoxicity assay and shown to significantly enhance the reversal of ABCB1-mediated MDR. In addition, the compound activated the ABCB1-mediated ATP hydrolysis and inhibited the photolabeling of ABCB1 with [125I]-iodoarylazidoprazosin. Furthermore, the compound also reversed the resistance to paclitaxel without increasing the toxicity in the ABCB1-overexpressing KB-V1 cell xenograft model. Overall, we concluded that the newly identified phenethylisoquinoline alkaloid reversed ABCB1-mediated MDR through direct interaction with the substrate-binding site of ABCB1. These findings may contribute to the development of more potent and less toxic ABCB1 modulators, which could overcome ABCB1-mediated MDR.

Abstract 3242: Synthetic analogs of curcumin as modulators of multidrug resistance-linked ABC transporters

Cancer patients often develop resistance to anticancer drugs. ATP-binding cassette (ABC) transporter-mediated drug efflux is one of the mechanisms responsible for development of resistance to anticancer drugs. The present study investigates the use of curcumin, a natural product and a dietary constituent of turmeric, which inhibits the function of three ABC drug transporters including ABCB1, ABCC1 and ABCG2. However, limited bioavailability of curcumin prevents its use for modulation of the function of these transporters in the clinic. We focused on curcumin analogs that were synthesized at Tohoku University and have been shown to exhibit higher bioavailability than natural curcumin to test whether the synthetic analogs also inhibit the function of ABC drug transporters. To investigate this, KB-V1 and K562/BCRP cell lines overexpressing ABCB1 and ABCG2 were used for the experiments. For these studies, we screened nineteen synthetic analogs of curcumin for their effect on the transport function of ABCB1 and ABCG2 by flow cytometry. Four curcumin analogs, GO-Y030, GO-Y078, GO-Y168 and GO-Y172 inhibited efflux of mitoxantrone mediated by ABCG2 and sensitized ABCG2-expressing K562 leukemic cells to the anticancer drug, SN-38 in cell toxicity assays. Some of the curcumin analogs (GO-Y030, GO-Y078, GO-Y172) stimulated ATPase activity of ABCG2 at nanomolar concentrations (EC50 = 480 ± 0.06, 790 ± 0.10, 930 ± 0.12 nM). In addition, GO-Y030, GO-Y078, GO-Y168, GO-Y172 analogs also inhibited photolabeling of ABCG2 in MCF-7-FL plasma membranes with iodoarylazidoprazosin, which is transported by this transporter. These data demonstrate that similar to curcumin, synthetic curcumin analogs also interact at the drug-binding pocket of ABCG2. In aggregate, these results suggest that non-toxic synthetic curcumin analogs with increased bioavailability may be useful to reverse ABCG2-mediated resistance to anticancer agents. Citation Format: Megumi Obara, Shinobu Ohnuma, Eduardo E. Chufan, Masaharu Ishida, Katsuyoshi Kudoh, Norihiko Sugisawa, Hideo Ohtsuka, Takeshi Naitoh, Hiroyuki Shibata, Yoshiharu Iwabuchi, Suresh V. Ambudkar, Michiaki Unno. Synthetic analogs of curcumin as modulators of multidrug resistance-linked ABC transporters [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3242. doi:10.1158/1538-7445.AM2017-3242