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Abnormal activation of the nuclear factor-kappa B (NF-κB) signaling pathway is closely implicated in triple-negative breast cancer growth, metastasis, and tumor immune escape. In this study, the anti-cancer effects of icariin, a natural flavonol glycoside, toward breast cancer cells and the underlying mechanisms were investigated. This investigation showed that icariin selectively inhibited proliferation and triggered apoptosis in breast cancer cells in a concentration- and time-dependent manner, but exhibited little cytotoxicity in normal breast cells. Moreover, icariin induced cell apoptosis via a mitochondria-mediated pathway, as indicated by the upregulated ratio of Bax/Bcl-2 and reactive oxygen species induction. Importantly, icariin impaired the activation of the NF-κB/EMT pathway, as evidenced by upregulation of SIRT6, resulting in inhibition of migration and invasion of breast cancer cells. Additionally, oss-128167, an inhibitor of SIRT6, dramatically attenuated anti-migration and anti-invasion effects of icariin. Transcriptomic analysis verified that impairment of NF-κB led to the selective function of icariin in breast cancer cells. Notably, icariin exhibited a significant tumor growth inhibition and anti-pulmonary metastasis effect in a tumor mouse model of MDA-MB-231 and 4T1 cells by regulating the tumor immunosuppressive microenvironment. Together, these results showed that icariin could effectively trigger apoptosis and inhibit the migration of breast cancer cells via the SIRT6/NF-κB signaling pathway, suggesting that icariin might serve as a potential candidate drug for the treatment of breast cancer., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Osteosarcoma is the most common primary malignancy of bone and characterized by an appendicular primary tumor with a high rate of metastasis to the lungs. Unfortunately, there is no effective strategy to treat osteosarcoma in current clinical practice. In this study, the anticancer effects and potential mechanisms of nifuroxazide, an oral nitrofuran antibiotic, on two osteosarcoma cell lines were investigated. The results of the antiproliferative activity in vitro showed that nifuroxazide inhibited cell proliferation of UMR106 and MG63 cells in a dose- and time-dependent manner. Interestingly, nifuroxazide showed low toxicity to non-tumor cells (HEK 293 T). In addition, ROS-mitochondrial mediated apoptosis was observed after treatment of nifuroxazide. Moreover, nifuroxazide could significantly inhibit osteosarcoma cells migration and invasion via p-Stat3, MMP-2 and MMP-9 mediated signaling pathway. Taken together, our results suggested that nifuroxazide could be a promising agent for osteosarcoma treatment by inhibiting cell proliferation, inducing cell apoptosis and impairing cell migration and invasion.

Targeting apoptotic pathways in tumor cells is recognized as a potent anticancer strategy. However, monotherapies that target a single apoptotic pathway often do not meet expectations and the nonspecific and uncontrolled activation of apoptotic pathways can overshadow potential application prospects. Here, a novel tumor‐microenvironment‐activated nano‐artificial virus (TMAN) with hierarchically responsive capacity is fabricated and loaded with the plasmid encoding tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) and mitochondria‐targeted red fluorescent phototoxic protein (KillerRed) simultaneously for precise and controllable exogenous and endogenous apoptosis coactivation. The inert TMAN is endowed with in vivo longevity and undergoes orderly acidity‐triggered deshielding of a masking layer, enzyme‐responsive charge‐reversal, and oxidative stress‐sensitive structural fragmentation in the tumor extra/intracellular microenvironment to exert precise tumor recognition, deep penetration, cellular internalization, rapid endosomes escape, and effective gene release ability, leading to the effective and tumor‐specific delivery of payloads. Given the virtues of TMAN, a favorable collaboration of TRAIL‐triggered exogenous apoptosis and mitochondria‐targeted KillerRed induced endogenous apoptosis is achieved synchronously under the control of light irradiation, thus remarkably improving antitumor efficacy with minimal toxicity. Taken together, this strategy highlights the significance of exogenous and endogenous apoptosis coactivation in cancer treatments and offers a promising paradigm for precise exo/endogenous dual‐augmented antitumor therapy. [ABSTRACT FROM AUTHOR]

With the increasing aging population, cancer has become one of the leading causes of death worldwide, and the number of cancer cases and deaths is only anticipated to grow further. Long non-coding RNAs (lncRNAs), which are closely associated with the expression level of downstream genes and various types of bioactivity, are regarded as one of the key regulators of cancer cell proliferation and death. Cell death, including apoptosis, necrosis, autophagy, pyroptosis, and ferroptosis, plays a vital role in the progression of cancer. A better understanding of the regulatory relationships between lncRNAs and these various types of cancer cell death is therefore urgently required. The occurrence and development of tumors can be controlled by increasing or decreasing the expression of lncRNAs, a method which confers broad prospects for cancer treatment. Therefore, it is urgent for us to understand the influence of lncRNAs on the development of different modes of tumor death, and to evaluate whether lncRNAs have the potential to be used as biological targets for inducing cell death and predicting prognosis and recurrence of chemotherapy. The purpose of this review is to provide an overview of the various forms of cancer cell death, including apoptosis, necrosis, autophagy, pyroptosis, and ferroptosis, and to describe the mechanisms of different types of cancer cell death that are regulated by lncRNAs in order to explore potential targets for cancer therapy. [ABSTRACT FROM AUTHOR]

Gene therapy is an efficient and promising approach to treat malignant tumors. However, protecting the nucleic acid from degradation in vivo and efficient delivering it into tumor cells remain challenges that require to be addressed before gene therapy could be applied in clinic. In this study, we prepared novel polyethyleneimine-RRRRRRRR(R8)-heparin (HPR) nanogel as an efficient gene delivery system, which consists of heparin and cell penetrating peptide R8 grafted low-molecule-weight polyethyleneimine (PEI). Due to the shielding effect of heparin, crosslinking PEI-R8 with heparin was designed to diminish the toxicity of the gene delivery system. Meanwhile, a partial of R8 peptide which located on the surface of HPR nanogel could significantly enhance the cellular uptake. The formed HPR/pDNA complex exhibited effective endolysosomal escape, resulting in a high-efficiency transfection. Furthermore, the HPR could deliver the plasmid which could transcribe human TNF-related apoptosis inducing ligand (phTRAIL), into HCT-116 cells and induce significant cell apoptosis. In addition, HPR/phTRAIL complex showed satisfactory antitumor activity in abdominal metastatic colon carcinoma model. Finally, the antitumor mechanism of HPR/phTRAIL was also explored by western blot and histological analysis. The above results suggested that the HPR nanogel could serve as a promising gene delivery system. [ABSTRACT FROM AUTHOR]

To develop injectable formulation and improve the stability of curcumin (Cur), Cur was encapsulated into monomethyl poly (ethylene glycol)-poly (ε-caprolactone)-poly (trimethylene carbonate) (MPEG-P(CL-co-TMC)) micelles through a single-step solid dispersion method. The obtained Cur micelles had a small particle size of 27.6 ± 0.7 nm with polydisperse index (PDI) of 0.11 ± 0.05, drug loading of 14.07 ± 0.94%, and encapsulation efficiency of 96.08 ± 3.23%. Both free Cur and Cur micelles efficiently suppressed growth of CT26 colon carcinoma cells in vitro. The results of in vitro anticancer studies confirmed that apoptosis induction and cellular uptake on CT26 cells had completely increased in Cur micelles compared with free Cur. Besides, Cur micelles were more effective in suppressing the tumor growth of subcutaneous CT26 colon in vivo, and the mechanisms included the inhibition of tumor proliferation and angiogenesis and increased apoptosis of tumor cells. Furthermore, few side effects were found in Cur micelles. Overall, our findings suggested that Cur micelles could be a stabilized aqueous formulation for intravenous application with improved antitumor activity, which may be a potential treatment strategy for colon cancer in the future. [ABSTRACT FROM AUTHOR]