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The antitumor efficacy of Chinese herbal medicines has been widely recognized. Leading compounds such as sterols, glycosides, flavonoids, alkaloids, terpenoids, phenylpropanoids, and polyketides constitute their complex active components. The antitumor monomers derived from Chinese medicine possess an attractive anticancer activity. However, their use was limited by low bioavailability, significant toxicity, and side effects, hindering their clinical applications. Recently, new chemical entities have been designed and synthesized by combining natural drugs with other small drug molecules or active moieties to improve the antitumor activity and selectivity, and reduce side effects. Such a novel conjugated drug that can interact with several vital biological targets in cells may have a more significant or synergistic anticancer activity than a single‐molecule drug. In addition, antitumor conjugates could be obtained by combining pharmacophores containing two or more known drugs or leading compounds. Based on these studies, the new drug research and development could be greatly shortened. This study reviews the research progress of conjugates with antitumor activity based on Chinese herbal medicine. It is expected to serve as a valuable reference to antitumor drug research and clinical application of traditional Chinese medicine. [ABSTRACT FROM AUTHOR]

Enzyme‐responsive and biocompatible supramolecular nanocarriers (NCs) have attracted intensive attention in the field of biomaterials, and have found many feasible applications, particularly for controlling drug‐release at specific anchor sites where the enzyme is overexpressed. However, the introduction of specific enzyme‐responsive sites in drug nanocarriers that can be enzymatically triggered to release drugs within tumor cells remains a challenge. In this manuscript, an enzyme‐responsive supramolecular nanoparticle, (SBE)7m‐β‐CD ⊃ PS NPs is successfully prepared, based on inducing aggregation of negatively charged cyclodextrin toward positively charged protein. The obtained nanoparticles showed trypsin‐trigger disassemble behavior that is considered as drug vehicles to load antitumor drug celastrol (CSL). Furthermore, CSL‐loaded NPs exhibit controlled release behavior of CSL in response to trypsin (TPS) stimulation. Notably, cell biology experiments reveal that loading CSL by (SBE)7m‐β‐CD ⊃ PS NPs not only reduces cytotoxicity for normal cells but also presents a similar therapeutic effect of free CSL for five tumor cells. The obtained nanoparticle appears to hold practical potential for the controllable release of CSL in tumor cells. [ABSTRACT FROM AUTHOR]

Tissue‐clearing technology is an emerging imaging technique currently utilized not only in neuroscience research but also in cancer research. In our previous reports, tissue‐clearing methods were used for the detection of metastatic tumors. Here, we showed that the cell cycles of primary and metastatic tumors were visualized by tissue‐clearing methods using a reporter system. First, we established cancer cell lines stably expressing fluorescent ubiquitination‐based cell cycle indicator (Fucci) reporter with widely used cancer cell lines A549 and 4T1. Fluorescence patterns of the Fucci reporter were investigated in various tumor inoculation models in mice. Interestingly, fluorescence patterns of the Fucci reporter of tumor colonies were different between various organs, and even among colonies in the same organs. The effects of antitumor drugs were also evaluated using these Fucci reporter cells. Of the three antitumor drugs studied, 5‐fluorouracil treatment on 4T1‐Fucci cells resulted in characteristic fluorescent patterns by the induction of G2/M arrest both in vitro and in vivo. Thus, the combination of a tissue‐clearing method with the Fucci reporter is useful for analyzing the mechanisms of cancer metastasis and drug resistance. [ABSTRACT FROM AUTHOR]

Electrochemotherapy is an effective strategy for the treatment of solid tumors by exposing tumor cells to electric fields to enhance the bioactivity of non‐permeable or low permeable anticancer drugs, such as cisplatin. To understand the improved efficiency of cisplatin in the electrochemotherapy, the effects of oriented external electric fields (OEEFs) on the geometric structure and relevant electronic properties of cisplatin have been systemically investigated by density functional theory (DFT) computations in this work. Our results reveal that the presence of selective OEEFs on cisplatin can not only weaken its Pt‐Cl bonds, but also enhance the intramolecular charge transfer in it, which effectively accelerates the critical hydrolysis step involved in the mechanism of biological activity for this drug. Moreover, the chosen OEEFs can facilitate the attack of the singly aquated cis‐[Pt(NH3)2(H2O)Cl]+ on DNA, and enlarge the water solubility of cisplatin and its aquated product. These OEEF‐induced geometric and electronic modifications can indeed help to improve the antitumor activity of cisplatin, which provides a deeper insight into the higher efficacy of electrochemotherapy than traditional chemotherapy from a molecular point of view. [ABSTRACT FROM AUTHOR]

Background: CD47 is a widely expressed transmembrane protein located on the surface of somatic cells. It mediates a variety of cellular processes including apoptosis, proliferation, adhesion, and migration. An important role for CD47 is the transmission of a "Don't eat me" signal by interacting with SIRPα on the macrophage surface membrane, thereby preventing the phagocytosis of normal cells. However, cancer cells can take advantage of this autogenous signal to protect themselves from phagocytosis, thus enabling immune escape. Blocking the interaction between CD47 and SIRPα has proven to be effective in removing cancer cells. The treatment of various cancers with CD47 monoclonal antibodies has also been validated. Methods: We designed and synthesized a peptide (RS17), which can specifically bind to CD47 and block CD47‐SIRPα signaling. The affinity of RS17 for CD47‐expressing tumor cells was determined, while the inhibition of CD47‐SIRPα signaling was evaluated in vitro and in vivo. Results: The results indicated that RS17 significantly promotes the phagocytosis of tumor cells by macrophages and had a similar therapeutic effect compared with a positive control (CD47 monoclonal antibodies). In addition, a cancer xenograft mouse model was established using CD47‐expressing HepG2 cells to evaluate the effect of RS17 on tumor growth in vivo. Using ex vivo and in vivo mouse models, RS17 demonstrated a high inhibitory effect on tumor growth. Conclusions: Based on our results, RS17 may represent a novel therapeutic peptide for cancer therapy. [ABSTRACT FROM AUTHOR]

Management of bone metastasis is becoming increasingly important. Thus, local and systemic treatment options have been developed for control. Although systemic administration of anticancer agents is effective for bone metastasis, it is often stopped because of poor general conditions or side effects. Therefore, it is highly desirable to develop a more effective and safer local treatment for bone metastasis. The purpose of the current study was to investigate the antitumor effects and safety of gelatin hydrogel microspheres incorporating cisplatin (GM‐CDDP), which we developed as a sustained release system without harmful substances. First, we assessed GM‐CDDP for its in vitro degradability and potential for sustained release. Second, in vivo antitumor and side effects were evaluated using a murine bone metastasis model of MDA‐MB‐231 human breast cancer cells incorporating GFP. In vitro, initial bursts were observed within 2 h and CDDP was released gradually with gelatin hydrogel degradation, which reached 100% at 48 h. In vivo, local administration of GM‐CDDP (2 mg/kg) significantly suppressed tumor growth and bone osteolysis compared with the control, and local and systemic administration of free CDDP (2 mg/kg; p < 0.05). Local administration of GM‐CDDP significantly reduced loss of body weight and elevation of blood urea nitrogen compared with the systemic administration of free CDDP (p <.05). The current study suggests that local administration of GM‐CDDP achieves higher antitumor effects with a potential for lesser side effects compared with local or systemic administration of free CDDP. [ABSTRACT FROM AUTHOR]

Background: Recombinant human calcineurin B subunit (rhCNB) has been shown to be an immune‐stimulatory protein promoting cytokine production and inducing phenotypic maturation of Dendritic cells (DCs). In vivo, it has good antitumor efficacy, and has potential as an antitumor drug. Exogenous rhCNB was found to be internalized into tumor cells via the Toll‐like receptor 4 (TLR4) complex, but it was not known whether its immuno‐modulatory and antitumor functions involved entry by this same route. Methods: The production and secretion of the cytokines and chemokines in innate immune cells induced by rhCNB were determined by ELISA, and the expression of CD40, CD80, CD86, and MHCII was analyzed by FACs. Experimental Lewis lung cancer (LLC) model was prepared in C57 BL/6 wild‐type (WT) mice, TLR4−/− mice or their littermates by the inoculation of LLCs in their right armpit, and then administrated daily intraperitoneal injections (0.2 mL) of normal saline, rhCNB 20 mg/kg, and rhCNB 40 mg/kg, respectively. Results: Recombinant human calcineurin B subunit promoted the production of antitumor cytokines by innate immune cells, and culture supernatants of rhCNB‐stimulated immune cells induced apoptosis of LLCs. In addition, rhCNB up‐regulated CD40, CD80, CD86, and MHCII expression in macrophages and DCs in TLR4+ cells but failed to do so in TLR4 deficient cells. rhCNB also induced the formation of CD4+ and CD8+T cells in splenocytes from WT mice, but not from TLR4‐deficient littermates. Intraperitoneal administration of WT C57BL/6 mice with rhCNB resulted in a 50% reduction in LLC tumor growth, but failed to inhibit tumor growth in TLR4−/− littermates. Conclusions: The in vivo antitumor and immunomodulatory effects of rhCNB are mediated by the TLR4. This conclusion is important for the further understanding and development of rhCNB as an antitumor drug. [ABSTRACT FROM AUTHOR]