Primary liver cancer is the sixth most prevalent cancer worldwide and ranked in third for cancer-related mortality rate. Hepatocellular carcinoma (HCC) accounts for about 90% of all primary liver cancers. High vascularization of HCC implies the significance of angiogenesis in the development and pathogenesis of HCC. Several angiogenic pathways have been identified as being dysregulated in HCC, highlighting potential therapeutic targets for the treatment of HCC. In 2007, sorafenib was approved as the standard first-line treatment for advanced HCC, catapulting the therapeutic approach of HCC into the avenue of targeted therapy. In recent years, the approval of several novel targeted drugs and the progress in combination of immunotherapy and targeted therapies provide more alternatives for the treatment of HCC. The progress of anti-angiogenesis therapies in HCC over the past few decades is reviewed and the future prospect of anti-angiogenesis therapy for HCC is also discussed.

Tumor development is frequently accompanied by abnormal expression of multiple genomic genes, which can be broadly viewed as decreased expression of tumor suppressor genes and upregulated expression of oncogenes. In this process, epigenetic regulation plays an essential role in the regulation of gene expression without alteration of DNA or RNA sequence, including DNA methylation, RNA methylation, histone modifications and non-coding RNAs. Therefore, drugs developed for the above epigenetic modulation have entered clinical use or preclinical and clinical research stages, contributing to the development of antitumor drugs greatly. Despite the efficacy of epigenetic drugs in hematologic caners, their therapeutic effects in solid tumors have been less favorable. A growing body of research suggests that epigenetic drugs can be applied in combination with other therapies to increase efficacy and overcome tumor resistance. In this review, the progress of epigenetics in tumor progression and oncology drug development is systematically summarized, as well as its synergy with other oncology therapies. The future directions of epigenetic drug development are described in detail.

GABA is the most common inhibitory neurotransmitter in the vertebrate central nervous system. Synthesized by glutamic acid decarboxylase, GABA could specifically bind with two GABA receptors to transmit inhibition signal stimuli into cells: GABAA receptor and GABAB receptor. In recent years, emerging studies revealed that GABAergic signaling not only participated in traditional neurotransmission but was involved in tumorigenesis as well as regulating tumor immunity. In this review, we summarize the existing knowledge of the GABAergic signaling pathway in tumor proliferation, metastasis, progression, stemness, and tumor microenvironment as well as the underlying molecular mechanism. We also discussed the therapeutical advances in targeting GABA receptors to provide the theoretical basis for pharmacological intervention of GABAergic signaling in cancer treatment especially immunotherapy.

Pancreatic cancer is a malignant disease characterized by low survival and high recurrence rate, whose patients are mostly at the stage of locally advanced or metastatic disease when first diagnosed. Early diagnosis is particularly important because prognostic/predictive markers help guide optimal individualized treatment regimens. So far, CA19-9 is the only biomarker for pancreatic cancer approved by the FDA, but its effectiveness is limited by low sensitivity and specificity. With recent advances in genomics, proteomics, metabolomics, and other analytical and sequencing technologies, the rapid acquisition and screening of biomarkers is now possible. Liquid biopsy also occupies a significant place due to its unique advantages. In this review, we systematically describe and evaluate the available biomarkers that have the greatest potential as vital tools in diagnosing and treating pancreatic cancer.

Apolipoprotein C1 (APOC1) has been found to play an essential part in proliferation and metastasis of numerous cancers, but related mechanism has not been elucidated, especially its function and role in tumor immunity. Through systematic pan-cancer analysis, we identified that APOC1 was closely associated with the infiltration of various immune cells in multiple cancers. Besides, APOC1 was significantly co-expressed with the immune checkpoints, major histocompatibility complex (MHC) molecules, chemokines and other immune-related genes. Furthermore, single-cell sequencing analysis suggested that the vast majority of APOC1 was expressed in macrophages or tumor-associated macrophages (TAMs). Additionally, the expression of APOC1 was significantly related to the prognosis of different cancers. Since APOC1 was most significantly abnormally expressed in renal cell cancer (RCC), subsequent experiments were carried out in RCC to explore the role of APOC1 in tumor immunity. The expression of APOC1 was significantly elevated in the tumor and serum of RCC patients. Besides, APOC1 was mainly expressed in the macrophage and it was closely related to the immune cell infiltration of RCC. Co-culture with RCC cells could induce the generation of TAMs with M2 phenotype which be blocked by silencing APOC1. The expression of APOC1 was elevated in the M2 or TAMs and APOC1 promoted M2 polarization of macrophages through interacting with CD163 and CD206. Furthermore, macrophages overexpressing APOC1 promoted the metastasis of RCC cells via secreting CCL5. Together, these data indicate that APOC1 is an immunological biomarker which regulates macrophage polarization and promotes tumor metastasis.

Colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women worldwide. CRC is the second leading cause of cancer-related deaths. Although some progress in the treatment of CRC has been achieved, the molecular mechanism of CRC is still unclear. In this study, alcohol dehydrogenase 1C(ADH1C) was first identified as a target gene closely associated with the development of CRC by the comprehensive application of transcriptomics, proteomics, metabonomics and in silico analysis. The ADH1C mRNA and protein expression in CRC cell lines and tumor tissues was lower than that in normal intestinal epithelial cell lines and healthy tissues. Overexpression of ADH1C inhibited the growth, migration, invasion and colony formation of CRC cell lines and prevented the growth of xenograft tumors in nude mice. The inhibitory effects of ADH1C on CRC cells in vitro were exerted by reducing the expression of PHGDH/PSAT1 and the serine level. This inhibition could be partially reversed by adding serine to the culture medium. These results showed that ADH1C is a potential drug target in CRC.

Lung cancer is by far the leading cause of cancer death worldwide, and 85% of patients are diagnosed with non-small cell lung cancer (NSCLC), which is still very difficult to treat. Skp2 functions as an oncogene that participates in processes of many cancers. Here, we report a novel Skp2 inhibitor AAA-237 that binds to Skp2 protein and inhibits the proliferation of the NSCLC cells. We further investigated the anti-NSCLC mechanism of AAA-237 and found that it arrested the cell cycle at the G0/G1 phase by targeting Skp2 to reduce the degradation of p21Cip1 and p27Kip1 or by transcriptionally activating FOXO1 to increase the mRNA expression of p21Cip1 and p27Kip1. More importantly, we found that treatment of a high concentration AAA-237 could induce apoptosis of NSCLC cells and treatment of a low AAA-237 concentration for a longer time could induce senescence of NSCLC cells. Similar results were found in nude mice xenografted with A549 cells. AAA-237 inhibited tumor growth by inducing apoptosis and senescence in a dose-dependent manner. Considering these results, we propose that AAA-237 could be a promising therapeutic drug for treating patients with NSCLC.

Glioblastoma (GBM), a malignant brain tumor, is a world-wide health problem because of its poor prognosis and high rates of recurrence and mortality. Apolipoprotein C1 (APOC1) is the smallest of apolipoproteins, implicated in many diseases. Recent studies have shown that APOC1 promotes tumorigenesis and development of several types of cancer. In this study we investigated the role of APOC1 in GBM tumorigenesis. Using in silico assays we showed that APOC1 was highly expressed in GBM tissues and its expression was closely related to GBM progression. We showed that APOC1 protein expression was markedly increased in four GBM cell lines (U251, U138, A172 and U87) compared to the normal brain glia cell lines (HEB, HA1800). In U251 cells, overexpression of APOC1 promoted cell proliferation, migration, invasion and colony information, which was reversed by APOC1 knockdown. APOC1 knockdown also markedly inhibited the growth of GBM xenografts in the ventricle of nude mice. We further demonstrated that APOC1 reduced ferroptosis by inhibiting KEAP1, promoting nuclear translocation of NRF2 and increasing expression of HO-1 and NQO1 in GBM cells. APOC1 also induced ferroptosis resistance by increasing cystathionine beta-synthase (CBS) expression, which promoted trans-sulfuration and increased GSH synthesis, ultimately leading to an increase in glutathione peroxidase-4 (GPX4). Thus, APOC1 plays a key role in GBM tumorigenesis, conferring resistance to ferroptosis, and may be a promising therapeutic target for GBM.

The goal of this work was to develop a sensitive and accurate method based on high performance liquid chro-matography with tandem mass spectrometry (LC-MS) detection for determining the concentration of the Sino-menine derivative SWX in plasma and tissue of rat. Chromatographic separation was achieved on an Agilent SB-C18 (2.1*50 mm, 2.7 mu m) column. The mobile phase consisted of acetonitrile (solvent A) and 0.2 % formic acid in water (solvent B) with gradient elution as follows: 0-3 min, 50-90 % A, 3 min-3.01 min, 90-50 % A, 90 % A in 3.01 min-10 min. The flow rate was set to 0.3 mL/min. The column temperature was 40 degrees C, and the sample injection volume was 10 mu L. The calibration curve had good linearity in the range of 10 ng/mL to 600 ng/mL. Biological samples were prepared by protein precipitation with acetonitrile. The area under the curve (AUC) and the peak drug concentration (Cmax) were linearly related to SWX dose. After oral administration of 25, 50 and 100 mg/kg SWX and intravenous administration of 0.5 mg/kg SWX, respectively, the absolute bioavailability of SWX was estimated as 12.4 %, 12.2 % and 10.6 %. SWX was widely distributed in heart, liver, spleen, lung, kidney, brain, breast, and fat, especially in lung, liver, and spleen. Distribution of SWX in brain suggested that it can pass the blood-brain barrier. The method established in this study has the advantages of high recovery and good reproducibility, and was suitable for the determination of the content of Sinomenine derivatives, providing a reliable scientific tool for carrying out pharmacokinetics research, providing a reliable scientific resource.

Aminopeptidase N(APN/CD13), a Zn2+-dependent ectopeptidase localized on the cell surface, is widely considered to influence the invasion of tumor cells. We found that boroleucine and dino-leucine borate exhibited a strong inhibitory effect on the enzyme activity of aminopeptidase N. The tested assay indicated that both compounds had an anti-proliferative effect on triple-negative breast cancer cells. Wound healing assay, migration test and matrigel-coated transwell assay showed that both boroleucine and dino-leucine borate inhibited the migration and invasion of breast cancer cells. Immunoblot analysis showed that both compounds down-regulated the expression of matrix metalloproteinase-2/9. In the capillary tube formation assay of human umbilical vein endothelial cells (HUVECs), dino-leucine borate showed better antiangiogenic activity than ubenimex even at a low concentration (10 μM). Moreover, compared with ubenimex, the anti-metastatic activity of dino-leucine borate in vivo was similar to or even better than that of ubenimex in the H22 pulmonary metastasis mouse model. In this paper, we found the novel APN inhibitors to markedly suppress the enzyme activity of APN and inhibit the migration and invasion of tumor cells in vitro and in vivo.

Background Adrenocortical carcinoma (ACC) is an extremely rare, aggressive tumor with few effective therapeutic options or drugs. Mitotane (Mtn), which is the only authorized therapeutic drug, came out in 1970 and is still the only first-line treatment for ACC in spite of serious adverse reaction and a high recurrence rate. Methods By in silico analysis of the ACC dataset in the cancer genome atlas (TCGA), we determined that high expression levels of cyclin-dependent kinase-1 (CDK1) were significantly related to the adverse clinical outcomes of ACC. In vitro and in vivo experiments were performed to evaluate the role of CDK1 in ACC progression through gain and loss of function assays in ACC cells. CDK1 inhibitors were screened to identify potential candidates for the treatment of ACC. RNA sequencing, co-immunoprecipitation, and immunofluorescence assays were used to elucidate the mechanism. Results Overexpression of CDK1 in ACC cell lines promoted proliferation and induced the epithelial-to-mesenchymal transition (EMT), whereas knockdown of CDK1 expression inhibited growth of ACC cell lines. The CDK1 inhibitor, cucurbitacin E (CurE), had the best inhibitory effect with good time-and dose-dependent activity both in vitro and in vivo. CurE had a greater inhibitory effect on ACC xenografts in nude mice than mitotane, without obvious adverse effects. Most importantly, combined treatment with CurE and mitotane almost totally eliminated ACC tumors. With respect to mechanism, CDK1 facilitated the EMT of ACC cells via Slug and Twist and locked ACC cells into the G2/M checkpoint through interaction with UBE2C and AURKA/B. CDK1 also regulated pyroptosis, apoptosis, and necroptosis (PANoptosis) of ACC cells through binding with the PANoptosome in a ZBP1-dependent way. Conclusions CDK1 could be exploited as an essential therapeutic target of ACC via regulating the EMT, the G2/M checkpoint, and PANoptosis. Thus, CurE may be a potential candidate drug for ACC therapy with good safety and efficacy, which will meet the great need of patients with ACC.

细胞毒类抗肿瘤药物是目前治疗恶性肿瘤的主要手段之一,然而此类药物在杀死肿瘤细胞的同时,会对人体正常细胞(尤其是分裂增殖旺盛的细胞)产生毒副作用,其临床应用受到一定的限制.近年发现氨肽酶N抑制剂乌苯美司与抗肿瘤化疗药物有显著协同作用,能增强药物的治疗效果、减少化疗药物的毒副作用.该文概括了乌苯美司增强化疗药的抗肿瘤作用,通过抑制肿瘤干细胞自我更新、抑制自噬、诱导凋亡、增加宿主免疫力等途径逆转耐药的机制,论述了临床实验进展,进一步说明乌苯美司在治疗恶性肿瘤中可作为有效的辅助用药,为临床合理应用提供依据.

Multidrug resistance (MDR) of hepatocellular carcinoma (HCC) is a serious problem that directly hinders the effect of chemotherapeutics. In this study, we mainly explore the molecular mechanism of ROS-induced CD13 expression using hepatocarcinoma cells as the research object. We show that the drug of fluorouracil (5FU), epirubicin (EPI) and gemcitabine (GEM) can induce ROS generation, activate Ets2 and promote CD13 expression. Meanwhile, CD13 can activate NRF1 and up-regulate ROS scavenging genes transcription, such as SOD1, GPX1, GPX2 and GPX3, leading to down-regulation of intracellular ROS level and reducing the sensitivity of cells to chemotherapy agent. We also detected the anti-tumor effect of the combination therapy, CD13 inhibitor ubenimex and a variety of conventional anti-cancer drugs, such as 5FU, EPI, GEM, pemetrexed (Pem) and paclitaxel (PTX) were employed in combination. Ubenimex enhances the sensitivity of different chemotherapeutic agents and cooperates with chemotherapeutic agents to suppress tumor growth in vitro and in vivo . In general, overexpression of CD13 can lead to chemotherapy resistance, and CD13 inhibitor can reverse this effect. Combination of chemotherapy agent and ubenimex will become a potential treatment strategy for liver cancer resistance.

Background: Lung cancer is by far the leading cause of cancer death worldwide, and 85% of patients are non-small cell lung cancer (NSCLC). NSCLC is still very difficult to treat. Skp2 functions as an oncogene and participates in the processes of NSCLC. Here, we disclose a novel Skp2 inhibitor, which is firstly synthesized by our group based on our previous computer virtual screening and biomolecular interaction analysis (Biacore) technology screening. Methods: To unveil antitumor activity and underlying molecular mechanism of AAA-237, cell proliferation, migration and invasion assays, apoptosis, cell cycle, senescence, and xenograft mouse models were used.Results: AAA-237 inhibited the proliferation of NSCLC cells. AAA-237 regulated the process of epithelial–mesenchymal transition (EMT) by Skp2/Twist axis. Furthermore, AAA-237 induced arresting of cell cycle at G0/G1 phase by regulating the Skp2-Cip/Kip and PI3K/Akt-FOXO1 signaling pathways. More importantly, we found that treatment of high concentration AAA-237 could induce apoptosis of NSCLC cells via the mitochondrial pathway whereas treatment of low concentration AAA-237 for long-term could induce senescence of NSCLC cells by DNA damage. Senolytic drug quercetin could selectively eliminate senescent cells induced by AAA-237. In A549 xenograft nude mice model, AAA-237 dose-dependently inhibited the growth of tumor by inducing apoptosis and senescence.Conclusions: Taken together, we propose that AAA-237 is a promising therapeutic agent of NSCLC, especially when combined with senolytic drug.

目的 开发一种能准确、特异地评价目标化合物对人氨肽酶N的抑酶活性检测试剂盒.方法 验证试剂盒准确度、精密度、稳定性等性能指标,同时通过与同类的传统试剂盒进行米氏常数的评价确认该试剂盒的灵敏度.结果 精密度验证,试剂盒的CV=4.29％符合CV<15％的要求;准确度验证中,标准化残差δ*=1.747落在(-2,2)区间以内,在95％置信度内是正常实验点,数据准确可靠;酶源稳定性良好;线性范围宽,96孔板中氨肽酶N在加入量120μL时还能呈现良好的线性关系;该试剂盒米氏常数低于传统试剂盒,说明灵敏度高.结论 所开发的试剂盒主要的性能指标表现良好,能准确测定化合物对人源氨肽酶N的抑酶活性,其检测成本和可靠性优于现有上市产品,具有推广应用及开发价值.