Multidrug resistance (MDR) resulting from the overexpression of drug transporters such as P-glycoprotein (Pgp) increases the efflux of drugs and thereby limits the effectiveness of chemotherapy. To address this issue, this work develops an injectable hollow microsphere (HM) system that carries the anticancer agent irinotecan (CPT-11) and a NO-releasing donor (NONOate). Upon injection of this system into acidic tumor tissue, environmental protons infiltrate the shell of the HMs and react with their encapsulated NONOate to form NO bubbles that trigger localized drug release and serve as a Pgp-mediated MDR reversal agent. The site-specific drug release and the NO-reduced Pgp-mediated transport can cause the intracellular accumulation of the drug at a concentration that exceeds the cell-killing threshold, eventually inducing its antitumor activity. These results reveal that this pH-responsive HM carrier system provides a potentially effective method for treating cancers that develop MDR.

A pH‐Responsive Carrier System that Generates NO Bubbles to Trigger Drug Release and Reverse P‐Glycoprotein‐Mediated Multidrug Resistance

MicroRNAs (miRNAs) have been identified as important posttranscriptional regulators involved in various biological and pathological processes of cells, but their association with tumor chemoresistance has not been fully understood. We detected miR-15b expression in two lung adenocarcinoma cell lines, A549 and A549/CDDP, and then investigated the effects of miR-15b on the metastasis and the chemosensitivity of cancer cells, using both gain- and loss-of-function studies. The correlation between miR-15b level and chemoresistance was further investigated in clinical lung adenocarcinoma specimens. miR-15b was significantly upregulated in cisplatin-resistant lung adenocarcinoma A549/CDDP cells compared with parental A549 cells. miR-15b regulates epithelial–mesenchymal transition (EMT) and cisplatin resistance in vitro and modulates response of lung adenocarcinoma cells to cisplatin in vivo. Further studies identified phosphatidylethanolamine-binding protein 4 (PEBP4) as a direct and functional target of miR-15b. Small-interfering RNA-mediated PEBP4 knockdown revealed similar effects as that of ectopic miR-15b expression, whereas overexpression of PEBP4 attenuated the function of miR-15b in lung adenocarcinoma cells. Increased miR-15b expression was also detected in tumor tissues sampled from lung adenocarcinoma patients treated with cisplatin-based chemotherapy and was proved to be correlated with low expression of PEBP4, decreased sensitivity to cisplatin and poor prognosis. Our results suggest that upregulation of miR-15b could suppress PEBP4 expression and in turn contribute to chemoresistance of lung adenocarcinoma cells to cisplatin.

miR-15b regulates cisplatin resistance and metastasis by targeting PEBP4 in human lung adenocarcinoma cells

Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes that catalyze the addition of poly(ADP-ribose) (PAR) subunits onto themselves and other acceptor proteins. PARPs are known to function in a large range of cellular processes including DNA repair, DNA replication, transcription and modulation of chromatin structure. Inhibition of PARP holds great potential for therapy, especially in cancer. Several PARP1/2/3 inhibitors (PARPi) have had success in treating ovarian, breast and prostate tumors harboring defects in the homologous recombination (HR) DNA repair pathway, especially BRCA1/2 mutated tumors. However, treatment is limited to specific sub-groups of patients and resistance can occur, limiting the use of PARPi. Poly(ADP-ribose) glycohydrolase (PARG) reverses the action of PARP enzymes, hydrolysing the ribose-ribose bonds present in poly(ADP-ribose). Like PARPs, PARG is involved in DNA replication and repair and PARG depleted/inhibited cells show increased sensitivity to DNA damaging agents. They also display an accumulation of perturbed replication intermediates which can lead to synthetic lethality in certain contexts. In addition, PARG is thought to play an important role in preventing the accumulation of cytoplasmic PAR and therefore parthanatos, a caspase-independent PAR-mediated type of cell death. In contrast to PARP, the therapeutic potential of PARG has been largely ignored. However, several recent papers have demonstrated the exciting possibilities that inhibitors of this enzyme may have for cancer treatment, both as single agents and in combination with cytotoxic drugs and radiotherapy. This article discusses what is known about the functions of PARP and PARG and the potential future implications of pharmacological inhibition in anti-cancer therapy.

/pdf/poly-adp-ribose-glycohydrolase-parg-vs-poly-adp-ribose-2qj0hx9mf8.pdf

Poly(ADP-Ribose) Glycohydrolase (PARG) vs. Poly(ADP-Ribose) Polymerase (PARP) - Function in Genome Maintenance and Relevance of Inhibitors for Anti-cancer Therapy.

Is thoracoscopic pneumonectomy safe

Cell adhesion molecule 1 (CADM1/TSLC1), a putative tumor suppressor involving in cell adhesion, proliferation and apoptosis, is frequently inactivated in several carcinomas due to promoter hypermethylation. But alterations of CADM1/TSLC1 in colorectal carcinogenesis and clinical significance have not been elucidated yet. The aim of this study was to determine the role of functional inactivation of CADM1/TSLC1 gene in colorectal tumorigenesis and its potential as a novel epigenetic marker for clinical assessment of patients with colorectal cancer. We measured CADM1/TSLC1 expression levels in 8 colorectal cancer cell lines, 54 primary colorectal carcinomas and their corresponding non-cancerous tissues by reverse transcription polymerase chain reaction, western blot analysis and immunohistochemistry. We analyzed CADM1/TSLC1 promoter methylation status by bisulfite genomic sequencing and the methylation special polymerase chain reaction, and evaluated its correlation with clinicopathological characteristics. All statistical tests were 2-sides. Downregulation of CADM1/TSLC1 expression was observed in 7 of 8 (88%) colorectal cancer cell lines and in 39 of 54 (72%) primary colorectal carcinomas. Hypermethylation of CADM1/TSLC1 promoter region occurred in 6 of 8 (75%) colorectal cancer cell lines and 32 of 54 (59%) primary colorectal carcinomas, and was correlated with advanced colorectal carcinoma. Epigenetic inactivation of CADM1/TSLC1 gene is a frequent alteration in development of colorectal cancer and can be a potential biomarker for molecular staging of patients with colorectal cancer.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.25356

CADM1/TSLC1 inactivation by promoter hypermethylation is a frequent event in colorectal carcinogenesis and correlates with late stages of the disease.

Frequent overexpression of CADM1/IGSF4 in lung adenocarcinoma.

Video-assisted thoracoscopic extrapleural pneumonectomy for malignant pleural mesothelioma

手術支援ロボットダヴィンチSサージカルシステムは，より複雑で細やかな手術操作を可能とし，3次元による正確な画像情報を取得できるため，より安全かつ侵襲の少ない手術を可能とするかもしれない．我々は肺癌症例に対し，このダヴィンチSサージカルシステムを使用し，肺葉切除＋縦隔リンパ節郭清を行った．症例は56歳女性．右上葉肺腺癌cT1bN0N0 stage IAに対し，右上葉切除＋縦隔リンパ節郭清を施行した．剥離操作はすべてダヴィンチシステム下に行い，術野展開，吸引操作とステープリングは助手が行った．手術時間は6時間48分，出血量は234gであった．多関節を有する器具は自由度が高く，胸腔内における剥離操作をより自然なものにする．これは，通常のVATSにおける直線的な器具での操作と比較して大きな利点であった．ダヴィンチシステムによるロボット支援は，今後のさらなるシステムの改良と相まって，これまで技術的に困難と考えられていた手術を可能とするかもしれない．

https://www.jstage.jst.go.jp/article/jacsurg/24/4/24_4_727/_pdf

Robot-assisted major lung resection using the da Vinci Surgical System: The first case in Japan

比較的稀だが重大な合併症である術後肺軸捻転の1例を経験したので報告する．症例は52歳の男性．経気管支肺生検にて腺癌と診断し，T2N1M0 c-Stage II Bのため左上葉切除術と縦隔リンパ節郭清術を施行した．術後1日目より胸部X線上左肺野の透過性低下を認め，術後3日目には発熱と炎症反応の異常高値を示した．気管支内視鏡検査にて左下幹の狭窄を認め，残存下葉の肺軸捻転を疑い再開胸術を施行した．肺は暗赤色で緊満し，気管支を軸に約180度捻転を起こしていた．残存肺の温存はできないと判断し，残存肺全摘を施行した．肺軸捻転を起こした要因として，肺靭帯の切離，縫合方向を考慮しない自動縫合器による気管支切離，および閉胸時に残存肺の位置確認を十分留意しなかったことが考えられた．

A case of lobar torsion after left upper lung lobectomy

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA

Introduction: Triple negative breast cancer (TNBC) is characterized by high proliferation and poor prognosis compared to other types of breast cancer. Treatment for TNBC needs to be improved because TNBC cells have no estrogen, progesterone and HER2 receptor, and approach for cure of TNBC is limited. TNBC patients with BRCA mutation have sensitivity to olaparib, a PARP inhibitor, inhibiting DNA repair. Therefore, treatment based on olaparib may be more effective for TNBC with BRCA mutation. In this study, we examined antitumor effects of olaparib to TNBC cells and combined effects with cytotoxic agents that could potentiate the antitumor effect of olaparib.

Methods: Sensitivity of olaparib to TNBC cell lines was examined by cell growth inhibition assay using CCK-8 kit and the combined antitumor effect with cytotoxic agents was evaluated by combination index. Intracellular poly (ADP-ribosyl) ation in MDA-MB-436 (MM436) cells was assessed by western blotting. Olaparib (50 mg/kg) and CPT-11 (15 and 30 mg/kg) were administered to Balb/c nude mice inoculated MM436 cells subcutaneously. The drug concentrations in plasma and tissues were measured by LC-MS/MS system (QTRAP5500, AB SCIEX).

Results: Inhibitory effect of cell growth by olaparib was 20-fold higher at a maximum in MM436 cells with BRCA mutation compared to other TNBC cell lines. Combination index of olaparib with CPT-11 in MM436 cells was lowest. In addition, CPT-11 caused Poly (ADP-ribosyl) ation higher than other cytotoxic agents in MM436 cells. In animal model, tumor growth was more inhibited by co-administration of olaparib and CPT-11 than olaparib or CPT-11 alone. Plasma concentration of these drugs and active metabolite SN-38 in any time period tended to be higher in co-administered animals than single-administered animals. In addition, Tumor tissue concentration of SN-38 at 2 hours after administration was higher in a group of combined administration than that of single administration.

Conclusion: The mechanisms of combined effect of olaparib and CPT-11 was that exposure of CPT-11 to TNBC cells with BRCA mutation caused PARP activation by its cytocidal action and synthetic lethality of olaparib worked more effectively. Furthermore, drug-drug interaction between olaparib and CPT-11 caused inhibiting activity of transporter function such as P-gp or BCRP and tumor tissue exposure levels increased. Therefore, the alteration of pharmacokinetics and pharmacodynamics contributes to the effect of combined treatment. The present results supported that olaparib treatment for TNBC with BRCA mutation had a potential of clinical benefit in combination with CPT-11.

Citation Format: Yuki Takashima, Jun Hashimoto, Yuka Kitamura, Shuichi Shimma, Yasuhiro Fujiwara, Fumiaki Koizumi, Kenji Tamura, Akinobu Hamada. Combined effects of olaparib and cytotoxic agents to triple negative breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1678. doi:10.1158/1538-7445.AM2014-1678

Abstract 1678: Combined effects of olaparib and cytotoxic agents to triple negative breast cancer cells

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