Arsenic trioxide, a cancer chemo drug hampers fibrotic liver regeneration by interrupting oxidative stress rekindling and stellate cell rejuvenation.

After withdrawal of liver toxic insult, the spontaneous regenerative potential of the liver is well reported in the literature. On the other hand, various molecules have been reported to promote as well as delay such natural regeneration. This current study investigates the involvement of arsenic trioxide (ATO) medication at chemotherapeutic dose on the spontaneous regeneration of the CCl4 induced fibrotic liver. Liver injury markers, such as albumin and SGOT, SGPT, and ALP activities, in serum indicated that ATO supplementation during liver regeneration hampers the rejuvenation process. The hepatic architecture as well as the degree of fibrosis by hematoxylin and eosin and Sirius red staining confirms the above findings. The reduced hepatic antioxidant system and elevated oxidative stress markers, such as lipid peroxidation and 8-hydroxy deoxy-guanosine-positive hepatocytes in ATO supplied rats, display the persistence of oxidative stress when compared with healthy controls and the normal regeneration model. Immuno-histochemical localization of Ki-67 indicates that mitotically active hepatocytes were fewer in the ATO given rats when compared with normal regeneration rats. Further delay in hepatic fibrinolysis was monitored by matrix metalloproteinase zymography assay in the ATO-given animals. Poly(ADP-ribose) polymerase 1 expression demonstrates elevated hepatocyte apoptosis with ATO. Furthermore, increased α-smooth muscle actin indicates that the stellate cells are in an activated state in ATO supplemented fibrotic animals. In conclusion, it's observed that ATO supplementation to the fibrotic liver delays oxidative stress revitalization and maintains stellate cells in the active form, thereby delaying liver regeneration, and the health status of the liver must be taken into account before administering drugs like ATO.

Using chemo-drugs or irradiation to break immune tolerance and facilitate immunotherapy in solid cancer.

The immunity is dual host-protective and tumor-promoting in cancer development and progression. Many immune suppressive cells and cytokines in microenvironment can prevent cytotoxic T lymphocytes (CTL) and natural killer cells (NK) from killing tumor cells. Chemotherapy drugs and irradiation have been reported helpful in breaking immune tolerance and creating microenvironment for adoptive cell therapy. Low-dose cyclophosphamide or gemcitabine therapy can selectively deplete T regulatory cells (Treg). Paclitaxel can alter cytokine network at the tumor site, and 5-fluorouracil shows a pronounced effect on myeloid-derived suppressor cells (MDSC) depletion. Local tumor irradiation and total body irradiation (TBI) can also affect tumor microenvironment and facilitate immunotherapy. In this review, we summarize the particular effects of these agents and methods on immunomodulation, as well as their potential values in immunotherapy. The combination with immunotherapy represents a novel therapeutic strategy.

Platinum-Coordinated Engineered Nanoreactors with O2 Self-Amplificationand On-Demand Cascade Chemo-Drug Synthesis for Self-Reinforcing Hypoxic Oncotherapy.

How to efficiently synthesize toxic chemo-drugs in the hypoxia tumor microenvironment still faces a huge challenge. Herein, we have tailored engineered vehicle-free nanoreactors by coordination-driven co-assembly of photosensitizer indocyanine green (ICG), transition metal platinum (Pt), and nontoxic 1,5-dihydroxynaphthalene (DHN) to self-amplify O2 and cascade chemo-drug synthesis in tumor cells for self-reinforcing hypoxic oncotherapy. Once vehicle-free nanoreactors are internalized into tumor cells, they show a serious instability that results in rapid disassembly and on-demand drug release under the stimuli of acidic lysosome and laser radiation. Notably, the released Pt can efficiently decompose the endogenous hydrogen peroxide (H2O2) into O2 to alleviate tumor hypoxia, which is conducive to enhancing the photodynamic therapy (PDT) efficiency of the released ICG. Complementarily, a large amount of the 1O2 generated by PDT can efficiently oxidize the released nontoxic DHN into the highly toxic chemo-drug juglone. Therefore, such vehicle-free nanoreactors can achieve intracellular on-demand cascade chemo-drug synthesis and self-reinforce photo-chemotherapeutic efficacy on the hypoxic tumor. On the whole, such a simple, flexible, efficient, and nontoxic therapeutic strategy will broaden the study of on-demand chemo-drug synthesis and hypoxic oncotherapy.

Comprehensive analysis for the immune related biomarkers of platinum-based chemotherapy in ovarian cancer.

BACKGROUND: Ovarian cancer (OC) is one of the most lethal gynecological malignancies. This study aimed to identify biomarkers that were sensitive to platinum-based chemotherapeutic agents and can be used in immunotherapy and explore the importance of their mechanisms of action. METHODS: RNA-seq profiles and clinicopathological data for OC samples were obtained from The Cancer Genome Atlas (TCGA) and cBioPortal platform, respectively. Platinum-sensitive and platinum-resistant OC samples in the TCGA cohort were selected based on the clinical information. RNA-seq data for 70 OC samples withSingle-sample gene set enrichment analysis (ssGSEA) and unsupervised clustering were used to classify OC patients from the TCGA cohort into clusters with different proportions of infiltrating immune cells. ESTIMATE analysis was used to assess the immune landscape among clusters. Differential expression, univariate Cox regression, and LASSO regression analyses were performed to construct prognostic model. Spearman correlation analysis was conducted to investigate the correlations among immune checkpoint inhibitors (ICIs) and risk score, half-maximal drug inhibitory concentration (IC50) and risk score. RESULTS: Using ssGSEA and unsupervised clustering, OC samples were divided into two clusters with different immune cell infiltration. Then, 1715 differentially expressed immune-related genes (DEIRGs) were identified between two clusters, 984 differentially expressed platinum-sensitive related genes (DEPSRGs) between 149 platinum-sensitive and 63 platinum-resistant OC samples were identified, and 5384 differentially expressed genes (DEGs) between 380 OC and 194 normal samples were detected from the TCGA cohort. Six biomarkers (GMPPB, SRPK1, STC1, PRSS16, HPDL, and SPTSSB) were detected to establish a prognostic model. The OC patients in the TCGA cohort were classified into high- and low-risk groups. The receive operating characteristic (ROC) curve was plotted and demonstrated that the prognostic model performed well with the area under ROC curve (AUC) greater than 0.6. The expressions of 5 ICIs, including CD200, TNFRSF18, CD160, CD200R1, and CD274 (PD-L1), were significantly different between two risk groups, and the risk score was significant negative associated with CTLA4, TNFRSF4, TNFRSF18, and CD274. Moreover, there were significant differences in IC50 of 10 chemo drugs between two risk groups, patients in the high-risk group could be more resistant to po0tinib, dasatinib, and neratinib. CONCLUSION: In summary, this study constructed a novel prognostic model based on six prognostic biomarkers, including GMPPB, SRPK1, STC1, PRSS16, HPDL, and SPTSSB, which can be utilized for predicting the prognosis of OC patients. These biomarkers were the potential therapeutic targets.

Research progress on the circRNA/lncRNA-miRNA-mRNA axis in gastric cancer.

Gastric cancer is one of the most common malignant tumours worldwide. Genetic and epigenetic alterations are key factors in gastric carcinogenesis and drug resistance to chemotherapy. Competing endogenous RNA (ceRNA) regulation models have defined circRNA/lncRNA as miRNA sponges that indirectly regulate miRNA downstream target genes. The ceRNA regulatory network is related to the malignant biological behaviour of gastric cancer. The circRNA/lncRNA-miRNA-mRNA axis may be a marker for the early diagnosis and prognosis of gastric cancer and a potential therapeutic target for gastric cancer. Exosomal ncRNAs play an important role in gastric cancer and are expected to be ideal biomarkers for the diagnosis, prognosis, and treatment of gastric cancer. This review summarizes the specific ceRNA regulatory network (circRNA/lncRNA-miRNA-mRNA) discovered in gastric cancer in recent years, which may provide new ideas or strategies for early clinical diagnosis, further development, and application.

Multiplex gene quantification as digital markers for extremely rapid evaluation of chemo-drug sensitivity.

Current administrations for precision drug uses are limited in evaluation speed. Here, we propose the use of multiplex gene-based digital markers for the extremely rapid personalized prediction of individual sensitivity to cancer drugs. We first screen the transcriptional profiles by applying two to three gene filters and scoring genes by their impact on drug sensitivity and finalize the gene lists by K-nearest neighbors cross-validation. The digital markers are cancer type dependent, are composed of tens to hundreds of gene expressions, and are rapidly quantified by reverse transcription quantitative real-time PCR (qRT-PCR) within 1-3 h after tumor sampling. The area under the receiver operating characteristic curve reached 0.88 when testing the performance of digital markers on organoids derived from colorectal cancer patient tumors. The algorithm and corresponding graphic user interface were developed to demonstrate the promise of digital markers for extremely rapid drug recommendation.

Co-delivery system of chemotherapy drugs and active ingredients from natural plants: a brief overview of preclinical research for cancer treatment.

Introduction: Many active ingredients from natural plants (AINPs) have been revealed to possess remarkable anticancer properties. Combination chemotherapy of chemo-drugs and AINPs has also proven to be more advantageous than individual chemo-drug treatment with respect to enhancing efficiency, alleviating toxicity, and controlling the development of multidrug resistance (MDR). Co-delivery is considered a promising method to effectively achieve and manage combination chemotherapy of chemo-drugs and AINPs, and various distinctive and functional co-delivery systems have been designed for these purposes to date.Areas covered: This review focuses on recent preclinical investigations of co-delivery systems for chemo-drugs and AINPs as new cancer treatment modalities. We particularly emphasize the apparent treatment advantages of these approaches, including augmenting efficiency, reducing toxicity, and controlling MDR.Expert opinion: There has already been notable progress in the application of combination chemotherapy with co-delivery systems loaded with chemo-drugs and AINPs based on results with cellular and animal models. The main challenge is to translate these successes into new anticancer compound preparations and promote their clinical application in practice. Nevertheless, continuous efforts with new designs of co-delivery systems remain essential, providing a foundation for future clinical research and development of new anticancer drugs.