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Carboplatin, a second-generation platinum agent, has been used as a cancer therapy for decades and exhibits strong anti-tumor activity. However, the wide application of carboplatin is largely limited due to its side effects, especially myelosuppression. Here, we combined carboplatin with curcumin, a natural product that improves tumor-induced anemia, for the treatment of fibrosarcoma to improve the side effects of carboplatin. We first examined the synergistic and attenuated effects of the two agents in a T241-bearing mouse model. The combination therapy caused no obvious synergistic effect, but curcumin significantly improved the survival rate of carboplatin-treated mice. Histologic analysis of the kidney and bone marrow revealed that curcumin improved carboplatin-induced myelosuppression but did not affect the kidney. To determine the mechanism involved, we introduced a probe derived from curcumin to identify its targets in bone marrow cells and the results provided us a clue that curcumin might affect the DNA repair pathway. Western blot analysis revealed that curcumin up-regulated BRCA1, BRCA2 and ERCC1 expression in bone marrow. In conclusion, curcumin attenuates carboplatin-induced myelosuppression by activating the DNA repair pathway in bone marrow cells.

Apigenin (APG) is an edible plant-derived flavonoid that shows modest antitumor activities in vitro and in vivo. APG treatment results in cell growth arrest and apoptosis in various types of tumors by modulating several signaling pathways. In the present study, we evaluated interactions between APG and TRAIL in non-small cell lung cancer (NSCLC) cells. We observed a synergistic effect between APG and TRAIL on apoptosis of NSCLC cells. A549 cells and H1299 cells were resistant to TRAIL treatment alone. The presence of APG sensitized NSCLC cells to TRAIL-induced apoptosis by upregulating the levels of death receptor 4 (DR4) and death receptor 5 (DR5) in a p53-dependent manner. Consistently, the pro-apoptotic proteins Bad and Bax were upregulated, while the anti-apoptotic proteins Bcl-xl and Bcl-2 were downregulated. Meanwhile, APG suppressed NF-κB, AKT and ERK activation. Treatment with specific small-molecule inhibitors of these pathways enhanced TRAIL-induced cell death, mirroring the effect of APG. Furthermore, using a mouse xenograft model, we demonstrated that the combined treatment completely suppressed tumor growth as compared with APG or TRAIL treatment alone. Our results demonstrate a novel strategy to enhance TRAIL-induced antitumor activity in NSCLC cells by APG via inhibition of the NF-κB, AKT and ERK prosurvival regulators.

Fas-associated protein with death domain (FADD), a pivotal adaptor protein transmitting apoptotic signals, is indispensable for the induction of extrinsic apoptosis. However, overexpression of FADD can form large, filamentous aggregates, termed death effector filaments (DEFs) by self-association and initiate apoptosis independent of receptor cross-linking. A mutant of FADD, which is truncated of the C-terminal tail (m-FADD, 182–205 aa) named N-FADD (m-FADD, 1–181 aa), can dramatically up-regulate the strength of FADD self-association and increase apoptosis. In this study, it was found that over-expression of FADD or N-FADD caused apoptosis of B16F10 cells in vitro, even more, N-FADD showed a more potent apoptotic effect than FADD. Meanwhile, Attenuated Salmonella Typhimurium strain VNP20009 was engineered to express FADD or N-FADD under the control of a hypoxia-induced NirB promoter and each named VNP-pN-FADD and VNP-pN-N-FADD. The results showed both VNP-pN-FADD and VNP-pN-N-FADD delayed tumor growth in B16F10 mice model, while VNP-pN-N-FADD suppressed melanoma growth more significantly than VNP-pN-FADD. Additionally, VNP-pN-FADD and VNP-pN-N-FADD induced apoptosis of tumor cells by activating caspase-dependent apoptotic pathway. Our results show that N-FADD is a more potent apoptotic inducer and VNP20009-mediated targeted expression of N-FADD provides a possible cancer gene therapeutic approach for the treatment of melanoma.

Scientific Reports 6: Article number: 29774; published online: 14 July 2016; updated: 02 September 2016 The Acknowledgements section in this Article is incomplete. “The authors are grateful to grants from the Doctoral Station Science Foundation from the Chinese Ministry of Education (20130091130003), the Nature Science Foundation of China (81421091), the Jiangsu Provincial Nature Science Foundation (BE2013630), the Open Project Programs from State Key Laboratory of Natural Medicines of China Pharmaceutical University (G140014) and The State Key Laboratory of Bioelectronics of Southeast University, the Bureau of Science and Technology of Changzhou (CZ20130011, CE20135013)”.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been known as a promising agent for cancer therapy due to its specific apoptosis-inducing effect on tumor cells rather than most normal cells. However, systemically delivered TRAIL suffers from a rapid clearance from the body with an extremely short half-life. Thermally responsive elastin-like polypeptides (ELPs) are a promising class of temperature sensitive biopolymers based on the structural motif found in mammalian tropoelastin and retain the advantages of polymeric drug delivery systems. We therefore expressed RGD-TRAIL fused with ELP (RGD-TRAIL-ELP) in E. coli. Purification of RGD-TRAIL-ELP was achieved by the conveniently inverse transition cycling (ITC). The purified RGD-TRAIL-ELP without any chemical conjugation was able to self-assemble into nanoparticle under physiological condition. Non-reducing SDS-PAGE results showed that trimer content of RGD-TRAIL-ELP increased 3.4-fold than RGD-TRAIL. Flow cytometry confirmed that RGD-TRAIL-ELP 3-fold enhanced apoptosis-inducing capacity than RGD-TRAIL. Single intraperitoneal injection of the RGD-TRAIL-ELP nanoparticle induced nearly complete tumor regression in the COLO-205 tumor xenograft model. Histological observation confirmed that RGD-TRAIL-ELP induced significant tumor cell apoptosis without apparent liver toxicity. These findings suggested that a great potential application of the RGD-TRAIL-ELP nanoparticle system as a safe and efficient delivery strategy for cancer therapy.

Bacteria-based living anticancer agents have emerged as promising therapeutics. However, the functional role of autophagy in bacterial cancer therapy has been little investigated. In this study, Salmonella VNP20009 induced autophagy in B16F10 cells, which is an unfavorable factor in bacterial cancer therapy. Inhibiting the induction of autophagy by chloroquine or siRNA in bacterial cancer therapy dose- and time-dependently promoted cell death. The combined therapy of VNP20009 and chloroquine not only enhanced the bacterial tumor targeting ability but also facilitated the infiltration of immune cells into the tumor. Our results showed that the combined therapy of VNP20009 and chloroquine could significantly inhibit tumor growth and prolong mouse survival time. This study provides a novel strategy for improving the anti-cancer efficacy of bacterial cancer therapy.

To date, the exact targets and mechanism of action of curcumin, a natural product with anti-inflammatory and anti-cancer properties, remain elusive. Here we synthesized a cell permeable curcumin probe (Cur-P) with an alkyne moiety, which can be tagged with biotin for affinity enrichment, or with a fluorescent dye for visualization of the direct-binding protein targets of curcumin in situ. iTRAQTM quantitative proteomics approach was applied to distinguish the specific binding targets from the non-specific ones. In total, 197 proteins were confidently identified as curcumin binding targets from HCT116 colon cancer cell line. Gene Ontology analysis showed that the targets are broadly distributed and enriched in the nucleus, mitochondria and plasma membrane, and they are involved in various biological functions including metabolic process, regulation, response to stimulus and cellular process. Ingenuity Pathway AnalysisTM (IPA) suggested that curcumin may exert its anticancer effects over multiple critical biological pathways including the EIF2, eIF4/p70S6K, mTOR signaling and mitochondrial dysfunction pathways. Functional validations confirmed that curcumin downregulates cellular protein synthesis, and induces autophagy, lysosomal activation and increased ROS production, thus leading to cell death.

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent, which kills cancer cells selectively, while leaving normal cells unharmed. However, the emerging resistance of tumor cells and patients to TRAIL-induced apoptosis limits its further application. In this study, we developed a chimeric protein Annexin V-TRAIL (designated as TP8) with higher efficacy than TRAIL both in vitro and in vivo. In vitro, the EC50 of TP8 on a series of tumor cells was much lower than wild-type TRAIL. Annexin V provided this recombinant protein with higher efficacy, while leaving tumor specificity of TRAIL unchanged since TP8 had no effects on normal cells. In vivo, TP8 effectively suppressed tumor growth and prolonged tumor doubling time and tumor growth delay time in mouse xenografts involving multiple cancer cell types including A549, Colo205 and Bel7402. This study provides a new rational strategy to treat TRAIL-resistant cancers.

The Src homology 2 domain-containing tyrosine phosphatase 2 (SHP-2) has been reported to have both tumor-promoting and tumor-suppressing roles in tumorigenesis. However, the role of SHP-2 in tumor immunity remains unclear. Here we observed progressively lower levels of phosphorylated SHP-2 in tumor-associated CD4(+) T cells during melanoma development in a murine model. Similarly, the levels of phosphorylated SHP-2 in the CD4(+) T cells of human melanoma specimens revealed a decrease paralleling cancer development. The CD4(+) T cell-specific deletion of SHP-2 promoted melanoma metastasis in mice. Furthermore, SHP-2 deficiency in CD4(+) T cells resulted in the increased release of inflammatory cytokines, especially IL-6, and the enhanced accumulation of tumor-promoting myeloid-derived suppressor cells (MDSCs) in tumor-bearing mice. An IL-6-neutralizing antibody reduced MDSC accumulation and inhibited tumor growth in CD4(+) T-cell-specific SHP-2-knockout mice. Our results suggest that SHP-2 in CD4(+) T cells plays an important role in preventing melanoma progression and metastasis.