Aminopeptidase N (APN/CD13) as a target molecule for scirrhous gastric cancer

Nohara, Shigeo; Kato, Kazunori; Fujiwara, Daisuke; Sakuragi, Naoya; Yanagihara, Kazuyoshi; Iwanuma, Yoshimi; Kajiyama, Yoshiaki

doi:10.1016/j.clinre.2015.11.003

Cited by 18 publications

(10 citation statements)

References 48 publications

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“…Indeed, there is a very active research on tumor stratification based on CD13 expression, and there are many reports in the literature indicating that CD13 expression is an unfavorable prognosis factor in a variety of cancers. Those tumors include pancreas [10] and colon cancers [11], non-small cell lung cancer [12,13], malignant pleural mesothelioma [14], hepatoblastoma [15], hepatocellular carcinoma [35], clear cell papillary renal cell carcinoma [36], scirrhous gastric cancer [37], lymphoplasmatic lymphoma [38], and soft tissue sarcoma [16]. Some of these tumors are rare and/or have poor prognosis, and new therapeutic approaches are urgently needed to increase patient's survival.…”

Section: Discussionmentioning

confidence: 99%

CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110

et al. 2020

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Background: In the search for novel antibody-drug conjugates (ADCs) with therapeutic potential, it is imperative to identify novel targets to direct the antibody moiety. CD13 seems an attractive ADC target as it shows a differential pattern of expression in a variety of tumors and cell lines and it is internalized upon engagement with a suitable monoclonal antibody. PM050489 is a marine cytotoxic compound tightly binding tubulin and impairing microtubule dynamics which is currently undergoing clinical trials for solid tumors. Methods: Anti-CD13 monoclonal antibody (mAb) TEA1/8 has been used to prepare a novel ADC, MI130110, by conjugation to the marine compound PM050489. In vitro and in vivo experiments have been carried out to demonstrate the activity and specificity of MI130110. Results: CD13 is readily internalized upon TEA1/8 mAb binding, and the conjugation with PM050489 did not have any effect on the binding or the internalization of the antibody. MI130110 showed remarkable activity and selectivity in vitro on CD13-expressing tumor cells causing the same effects than those described for PM050489, including cell cycle arrest at G2, mitosis with disarrayed and often multipolar spindles consistent with an arrest at metaphase, and induction of cell death. In contrast, none of these toxic effects were observed in CD13-null cell lines incubated with MI130110. Furthermore, in vivo studies showed that MI130110 exhibited excellent antitumor activity in a CD13-positive fibrosarcoma xenograft murine model, with total remissions in a significant number of the treated animals. Mitotic catastrophes, typical of the payload mechanism of action, were also observed in the tumor cells isolated from mice treated with MI130110. In contrast, MI130110 failed to show any activity in a xenograft mouse model of myeloma cells not expressing CD13, thereby corroborating the selectivity of the ADC to its target and its stability in circulation.

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Section: Discussionmentioning

confidence: 99%

CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110

et al. 2020

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“…Finally, CD13 is considered a viable target for cancer therapy [ 10 , 28 ] in view of its participation in processes such as angiogenesis, tumor cell migration, and invasiveness, and the fact that expression of CD13 is dysregulated in several types of cancer cells, contributing in several ways to the malignancy. Several drugs interfering with CD13 functions are being tested for the development of anticancer drugs [ 1 , 29 – 32 ].…”

Section: Discussionmentioning

confidence: 99%

Distinct Epitopes on CD13 Mediate Opposite Consequences for Cell Adhesion

Garay-Canales

Licona‐Limón

Ortega

2018

BioMed Research International

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CD13 is a membrane glycoprotein with aminopeptidase activity, expressed on several cell types, including myeloid cells (dendritic cells, monocytes, macrophages, neutrophils, etc.). CD13 participates in several functions such as proteolytic regulation of bioactive peptides, viral receptor, angiogenesis, and tumor metastasis. CD13 has also been proposed to participate in cell adhesion, as crosslinking of CD13 by certain CD13-specific antibodies induces homotypic aggregation of monocytes and heterotypic adhesion of monocytes to endothelial cells. We generated two monoclonal antibodies (mAbs C and E) that block homotypic aggregation of U-937 monocytic cells induced by CD13-specific mAb 452. Moreover, the mAbs cause detachment of cells whose aggregation was induced by CD13 crosslinking. Both mAbs also inhibit heterotypic adhesion of U-937 monocytes to endothelial cells. mAbs C and E recognize membrane CD13 but bind to epitopes different from that recognized by mAb 452. Crosslinking of CD13 by mAb C or E is required to inhibit adhesion, as monovalent Fab fragments are not sufficient. Thus, C and E antibodies recognize a distinct epitope on CD13, and binding to this epitope interferes with both CD13-mediated cell adhesion and enzymatic activity. These antibodies may represent important tools to study cell-cell interactions mediated by CD13 in physiological and pathological conditions.

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“…Based on the decrease in APN expression, ubenimex could be a potential treatment for the suppression of metastasis and invasion in bladder cancer cells. APN expression has been confirmed to be involved in various cellular processes, including cellular attachment, motility and invasion/metastasis of various malignancies ( 22 ). The inhibition of APN expression results in a significant decrease in the metastasis of T24 cell lines ( 4 ).…”

Section: Discussionmentioning

confidence: 99%

Ubenimex, an APN inhibitor, could serve as an anti‑tumor drug in RT112 and 5637 cells by operating in an Akt‑associated manner

Wang

Liu

et al. 2018

Mol Med Report

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Bladder cancer, a common urinary tract tumor, has high mortality and recurrence rates associated with metastasis. Aminopeptidase N (APN) expression and metastasis have been indicated to be associated with one another. Ubenimex may function as an APN inhibitor to inhibit the degradation of the extracellular matrix during tumorigenesis. Furthermore, APN has been widely used as an adjuvant therapy for the treatment of tumors; however, little information is available regarding the impact of ubenimex on patients. Autophagy is suggested to be important in the transformation and progression of cancer. Additionally, apoptosis, which leads to the rapid demolition of cellular organelles and structures, has also been suggested as an important factor. Thus, the present study investigated the role of ubenimex in inhibiting migration and invasion by downregulating APN expression levels to induce autophagic cell death and apoptosis in bladder cancer cells. RT112 and 5637 cell lines were treated with varying doses of ubenimex. Cell viability was measured by CCK8 colorimetry and flow cytometry. Using fluorescence microscopy, autophagic cell death was assessed using acridine orange/ethidium bromide staining. Furthermore, apoptotic cell death was assessed using flow cytometry and Trypan blue staining was used to evaluate the cell death rate. Protein expression was determined by western blot analysis. Matrigel invasion assays were exploited to assess the invasion capabilities of 5637 cells. Wound-healing migration assays and Matrigel migration assays were exploited to assess the migratory abilities of 5637 cells. Treatment with ubenimex was accompanied by decreased Akt expression, indicating that ubenimex may have similar functions to Akt inhibitors. Results also indicated that ubenimex inhibited cell migration and invasion in bladder cancer cells. Furthermore, ubenimex also induced autophagic cell death and apoptosis, which suggested that mixed programmed cell death occurred in ubenimex-treated bladder cancer cells. The results from the present study suggest that ubenimex may be a potential adjuvant therapy for the treatment of bladder cancer.

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Aminopeptidase N (APN/CD13) as a target molecule for scirrhous gastric cancer

Abstract: These data suggest that CD13 is a suitable cell surface candidate for targeted antibody-drug therapy of scirrhous gastric cancer.

Cited by 18 publications

References 48 publications

CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110

CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110

Distinct Epitopes on CD13 Mediate Opposite Consequences for Cell Adhesion

Ubenimex, an APN inhibitor, could serve as an anti‑tumor drug in RT112 and 5637 cells by operating in an Akt‑associated manner

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