Ultrasmall nanostructured drug based pH-sensitive liposome for effective treatment of drug-resistant tumor.

BACKGROUND: Cancer cells always develop ways to resist and evade chemotherapy. To overcome this obstacle, herein, we introduce a programmatic release drug delivery system that imparts avoiding drug efflux and nuclear transport in synchrony via a simple nanostructured drug strategy. RESULTS: The programmatic liposome-based nanostructured drugs (LNSD) contained two modules: doxorubicin (DOX) loaded into tetrahedral DNA (TD, ~ 10 nm) to form small nanostructured DOX, and the nanostructured DOX was encapsulated into the pH-sensitive liposomes. In the in vitro and in vivo studies, LNSD shows multiple benefits for drug resistance tumor treatment: (1) not only enhanced the cellular DOX uptake, but also maintained DOX concentration in an optimum level in resistant tumor cells via nanostructure induced anti-efflux effect; (2) small nanostructured DOX efficiently entered into cell nuclear via size depended nuclear-transport for enhanced treatment; (3) improved the pharmacokinetics and biodistribution via reducing DOX leakage during circulation. CONCLUSIONS: The system developed in this study has the potential to provide new therapies for drug-resistant tumor.

Progress of Antimicrobial Mechanisms of Stilbenoids.

Antimicrobial drugs have made outstanding contributions to the treatment of pathogenic infections. However, the emergence of drug resistance continues to be a major threat to human health in recent years, and therefore, the search for novel antimicrobial drugs is particularly urgent. With a deeper understanding of microbial habits and drug resistance mechanisms, various creative strategies for the development of novel antibiotics have been proposed. Stilbenoids, characterized by a C6-C2-C6 carbon skeleton, have recently been widely recognized for their flexible antimicrobial roles. Here, we comprehensively summarize the mode of action of stilbenoids from the viewpoint of their direct antimicrobial properties, antibiofilm and antivirulence activities and their role in reversing drug resistance. This review will provide an important reference for the future development and research into the mechanisms of stilbenoids as antimicrobial agents.

Nanomedicines as emerging platform for simultaneous delivery of cancer therapeutics: new developments in overcoming drug resistance and optimizing anticancer efficacy.

Development and formulation of an efficient and safe therapeutic regimen for cancer theranostics are dynamically challenging. The use of mono-therapeutic cancer regimen is generally restricted to optimal clinical applications, on account of drug resistance and cancer heterogeneity. Combinatorial treatments can employ multi-therapeutics for synergistic anticancer efficacy whilst reducing the potency of individual moieties and diminishing the incidence of associated adverse effects. The combo-delivery of nanotherapeutics can optimize anti-tumor efficacy while reversing the incidence of drug resistance, aiming to homogenize pharmacological profile of drugs, enhance circulatory time, permit targeted drug accumulation, achieve multi-target dynamic approach, optimize target-specific drug binding and ensure sustained drug release at the target site. Numerous nanomedicines/nanotherapeutics have been developed by having dynamic physicochemical, pharmaceutical and pharmacological implications. These innovative delivery approaches have displayed specialized treatment effects, alone or in combination with conventional anticancer approaches (photodynamic therapy, radiotherapy and gene therapy), while reversing drug resistance and potential off-target effects. The current review presents a comprehensive overview of nanocarrier aided multi-drug therapies alongside recent advancements, future prospects, and the pivotal requirements for interdisciplinary research.

Mechanism of Chinese Medicine Monomer Reversing Paclitaxel Resistance： A Review / 中国实验方剂学杂志

Paclitaxel is the first-line chemotherapy drug for a variety of cancers. However， the paclitaxel resistance greatly reduced the efficacy in the later treatment stage， which seriously increased the mortality and recurrence rate of cancer and limited the clinical application of paclitaxel. At present， Chinese medicine compound prescription， proprietary Chinese medicine， and Chinese medicine injection are widely used as the adjuvant chemotherapy drugs for the treatment of cancer in clinic. Chinese medicine has shown unique advantages in improving the efficacy of chemotherapy drugs and the prognosis of chemotherapy， and reducing the toxic and side effects. However， the specific mechanism and effective monomer composition of Chinese medicine for reversing the resistance of chemotherapy drugs are unclear， and the application of Chinese medicine in different types of cancer is also limited， which are worthy of further exploration. This review summarized the composition of Chinese medicine monomer with synergistic antitumor effect combined with paclitaxel in recent years. The specific mechanism and pharmacological activities of Chinese medicine monomer reversing paclitaxel resistance were classified. This review found that through acting on the membrane transport protein， Chinese medicine monomer promoted the accumulation of paclitaxel in tumor cells， inhibited the expressions of protein and metabolic enzyme related to multidrug resistance and the metabolism of paclitaxel， and regulated the levels of apoptosis genes and factors and apoptosis-related pathways to promote the inhibitory effect of paclitaxel on cell proliferation. Chinese medicine monomer also significantly improved paclitaxel chemotherapy sensitivity by regulating the expression levels of micro ribonucleic acid （microRNA） and long non-coding ribonucleic acid RNA （lncRNA）， inhibiting the characteristics of tumor stem cells and tumor metabolic reprogramming， improving tumor microenvironment， and triggering tumor cell death autophagy and oxidative stress response. This review provides a theoretical basis for clarifying the specific anti-tumor mechanism of Chinese medicine monomer combined with paclitaxel， which is of great significance for the development of new Chinese medicine and the clinical research of the drugs combined with paclitaxel， and has certain value for the application of Chinese medicine combined with other chemotherapy drugs.

APN/CD13 inhibitor Ubenimex: A molecular chaperone of antineoplastic chemotherapeutic drugs / 中国药理学通报

Cytotoxic anti-neoplastic drugs are a kind of chemotherapeutic drugs that directly kill or inhibit the growth and proliferation of tumor cells, and it is one of the main drugs for the treatment of malignant tumors. These drugs may have toxic side effects on normal cells of human body (especially those with strong division and proliferation) when they are used to kill tumor cells. And patients may usually have adverse reactions even at a normal dose when using this kind of drugs. Due to the strong toxic side effects of cytotoxic chemotherapeutic drugs, their clinical application is limited. In recent years it has been found that aminopeptidase N inhibitor Ubenimex has a significant synergistic effect with anti-neoplastic chemotherapeutic drugs, which has the advantages of enhancing the therapeutic effect of drugs and reducing the toxic side effects of chemotherapeutic drugs. This review enumerates that the combination of Ubenimex and a variety of cytotoxic drugs can enhance the anti-tumor effect of cytotoxic drugs and reduce the occurrence of adverse reactions. In addition, the mechanism of combined use of Ubenimex in reversing drug resistance is also introduced. At the same time, is is further confirmed the clinical value of Ubenimex as an effective adjuvant in the treatment of malignant tumors, so as to provide a basis for clinical application.

In silico identified targeted inhibitors of P-glycoprotein overcome multidrug resistance in human cancer cells in culture.

Failure of cancer chemotherapies is often linked to the over expression of ABC efflux transporters like the multidrug resistance P-glycoprotein (P-gp). P-gp expression in cells leads to the elimination of a variety of chemically unrelated, mostly cytotoxic compounds. Administration of chemotherapeutics during therapy frequently selects for cells that over express P-gp and are therefore capable of robustly exporting diverse compounds, including chemotherapeutics, from the cells. P-gp thus confers multidrug resistance to a majority of drugs currently available for the treatment of cancers and diseases like HIV/AIDS. The search for P-gp inhibitors for use as co-therapeutics to combat multidrug resistances has had little success to date. In a previous study (Brewer et al., Mol Pharmacol 86: 716-726, 2014), we described how ultrahigh throughput computational searches led to the identification of four drug-like molecules that specifically interfere with the energy harvesting steps of substrate transport and inhibit P-gp catalyzed ATP hydrolysis in vitro. In the present study, we demonstrate that three of these compounds reversed P-gp-mediated multidrug resistance of cultured prostate cancer cells to restore sensitivity comparable to naïve prostate cancer cells to the chemotherapeutic drug, paclitaxel. Potentiation concentrations of the inhibitors were <3 µmol/L. The inhibitors did not exhibit significant toxicity to noncancerous cells at concentrations where they reversed multidrug resistance in cancerous cells. Our results indicate that these compounds with novel mechanisms of P-gp inhibition are excellent leads for the development of co-therapeutics for the treatment of multidrug resistances.

Research progress on anti-tumor mechanisms of arsenic trioxide and its drug delivery system / 中草药

Arsenic trioxide, a mineral drug of Chinese medicine material medica with significant therapeutic effect, has been approved by USA Food and Drug Administration (FDA) for the treatment of acute promyelocytic leukemia. In recent years, it has also been found to have a great therapeutic effect on the treatment of solid tumors. The anti-tumor mechanisms mainly include promoting apoptosis, inhibiting Hedgehog signaling pathway, reversing drug resistance and inhibiting angiogenesis. However, the poor targeting ability in vivo, the rapid renal clearance rate, and the toxic and side effects of high dose on normal tissues of arsenic trioxide limit the application and clinical transformation for the treatment of solid tumor. On the basis of traditional nanoparticles, the novel drug delivery system improves the drug aggregation, controlling-release and diagnosis in tumor sites, which is of great significance in accurate treatment, improvement of bioavailability and reduction of toxic and side effects. Research progress on anti-tumor mechanisms of arsenic trioxide and its drug delivery system in recent years was summarized and analyzed in this paper, in order to provide ideas for the in-depth research and clinical application of arsenic trioxide.