Cisplatin and other DNA-damaging chemotherapeutics are widely used to treat a broad spectrum of malignancies. However, their application is limited by both intrinsic and acquired chemoresistance. Most mutations that result from DNA damage are the consequence of error-prone translesion DNA synthesis, which could be responsible for the acquired resistance against DNAdamaging agents. Recent studies have shown that the suppression of crucial gene products (e.g., REV1, REV3L) involved in the errorprone translesion DNA synthesis pathway can sensitize intrinsically resistant tumors to chemotherapy and reduce the frequency of acquired drug resistance of relapsed tumors. In this context, combining conventional DNA-damaging chemotherapy with siRNAbased therapeutics represents a promising strategy for treating patients with malignancies. To this end, we developed a versatile nanoparticle (NP) platform to deliver a cisplatin prodrug and REV1/ REV3L-specific siRNAs simultaneously to the same tumor cells. NPs are formulated through self-assembly of a biodegradable poly(lactide-coglycolide)-b-poly(ethylene glycol) diblock copolymer and a self-synthesized cationic lipid. We demonstrated the potency of the siRNA-containing NPs to knock down target genes efficiently both in vitro and in vivo. The therapeutic efficacy of NPs containing both cisplatin prodrug and REV1/REV3L-specific siRNAs was further investigated in vitro and in vivo. Quantitative realtime PCR results showed that the NPs exhibited a significant and sustained suppression of both genes in tumors for up to 3 d after a single dose. Administering these NPs revealed a synergistic effect on tumor inhibition in a human Lymph Node Carcinoma of the Prostate xenograft mouse model that was strikingly more effective than platinum monotherapy.siRNA delivery | chemosensitivity | combination therapy A dvances in genomics and cell biology have highlighted the heterogeneity and complexity of cancer. It is generally accepted that cancer is usually the result of a combination of interconnected disease pathways that may not be treated effectively with 1D therapeutic mechanisms (1). The inhibition of a pathway by a single-drug therapy often results in the emergence of drug resistance and tumor relapse, largely because of pathway redundancy, cross-talk, compensatory and neutralizing actions, and antitarget activities that commonly occur with single-drug cancer therapy (2). In some cases, relapse can result in the emergence of phenotypically distinct and possibly more virulent tumors. For example, treatment of prostatic adenocarcinoma with androgen ablation therapies, such as abiraterone or enzalutamide, results in the development of abiraterone or enzalutamide refractory castration-resistant prostate cancer that is phenotypically nonadenocarcinoma and represents a rare and often lethal form of prostate cancer with a neuroendocrine phenotype (3).Platinum agents are among the most widely used cytotoxic agents for cancer therapy. Cisplatin and other DNA adductforming chemotherapeutics caus...

The development of cancer drug resistance is a persistent clinical problem limiting the successful treatment of disseminated malignancies. However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. Error-prone translesional DNA synthesis (TLS) is known to underlie the mutagenic effects of numerous anticancer agents, but little is known as to whether mutation induced by this process is ultimately relevant to tumor drug resistance. Here, we use a tractable mouse model of B-cell lymphoma to interrogate the role of error-prone translesional DNA synthesis in chemotherapyinduced mutation and resistance to front-line chemotherapy. We find that suppression of Rev1, an essential TLS scaffold protein and dCMP transferase, inhibits both cisplatin-and cyclophosphamideinduced mutagenesis. Additionally, by performing repeated cycles of tumor engraftment and treatment, we show that Rev1 plays a critical role in the development of acquired cyclophosphamide resistance. Thus, chemotherapy not only selects for drug-resistant tumor population but also directly promotes the TLS-mediated acquisition of resistance-causing mutations. These data provide an example of an alteration that prevents the acquisition of drug resistance in tumors in vivo. Because TLS also represents a critical mechanism of DNA synthesis in tumor cells following chemotherapy, these data suggest that TLS inhibition may have dual anticancer effects, sensitizing tumors to therapy as well as preventing the emergence of tumor chemoresistance.DNA polymerase | cancer | chemotherapy | relapse T he development of acquired chemoresistance is a persistent clinical problem limiting the successful treatment of disseminated malignancies. Tumors that relapse following initial treatment frequently are refractory to subsequent administration of the initial drug regimen as well as to distinct sets of chemotherapeutics. Although a number of key pathways have been implicated in resistance to conventional chemotherapeutics, including enhanced drug efflux, increased drug metabolism, drug inactivation, enhanced DNA repair, and defects in apoptosis programs (1, 2), the mechanisms by which tumors develop drug resistance-causing mutations remains unclear.At its core, acquired chemoresistance represents the emergence of subpopulations of drug-resistant tumor cells, a phenomenon rooted in the inherent genetic heterogeneity of the tumor itself. This heterogeneity may occur as a consequence of tumor genetic instability, a process known to underlie tumor development in numerous malignancies. Alternatively, cancer therapy itself may promote mutation and subsequent chemoresistance in relapsed tumors. Support for the latter hypothesis comes from several observations. First, conventional chemotherapeutics can be highly mutagenic (3). In fact, considerable work has gone into highlighting the mutagenic properties of platinum-based and other DNA adduct-forming chemotherapeutics as well as the genes that act in the cellular res...

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BackgroundDue to the increasing number of long-term (≥5 years post diagnosis) colorectal cancer survivors, long-term quality of life of these patients is highly relevant. Several studies have reported a positive association between physical activity and quality of life in colorectal cancer survivors, however, so far no systematic review has been published which focuses on long-term colorectal cancer survivors.Material and methodsA systematic review was conducted using the databases PubMed, Web of Science, PsychINFO, and CINAHL. Studies which investigated associations between physical activity and quality of life in long-term colorectal cancer survivors were included.Results and conclusionTen articles based on seven studies were identified. Long-term colorectal cancer survivors who were physically active reported better quality of life than long-term survivors who were not physically active. Both, moderate to vigorous physical activity and lower levels like light physical activity were associated with higher quality of life. Most studies assessed the association between physical activity and quality of life cross-sectionally but one prospective study which measured physical activity and quality of life at three different points in time also found associations between physical activity and quality of life. The association between physical activity and quality of life seemed to be stronger among women than among men. The findings of this systematic review support an association between physical activity and quality of life in long-term colorectal cancer survivors. However, the evidence is limited as most studies were based on cross-sectional and observational design.Electronic supplementary materialThe online version of this article (10.1186/s12955-018-0934-7) contains supplementary material, which is available to authorized users.

In the previous research, we found that D609 (tricyclodecan-9-yl-xanthogenate) could induce human marrow stromal cell (hMSC) differentiation to neuron-like cells. In this study, to understand the possible mechanism, we sequentially investigated the changes of phosphatidylcholine-specific phospholipase C (PC-PLC) activity, the expression of Rb, the intracellular reactive oxygen species (ROS) levels, NADPH oxidase and superoxide dismutase (SOD) activities when D609 induced neuronal differentiation in rat mesenchymal stem cells (MSCs). The results showed that D609 obviously inhibited the activity of PC-PLC when it induced neuronal differentiation in rat MSCs. Simultaneously, ROS level and the activity of NADPH oxidase increased significantly, but the MnSOD and Cu/ZnSOD activities were not altered. Furthermore, the level of Rb protein was evidently elevated. Our data suggested that PC-PLC mediated neuronal differentiation of rat MSCs by elevating NADPH oxidase activity, ROS level, and up-regulating the expression of Rb protein.

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LDP has the advantages of shorter hospital stay and operative time, more rapid recovery and higher spleen-preserving rate as compared with ODP.

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