Synergetic effects of the combined action of carbon ions and the chemotherapy drug doxorubicin on HeLa cancer cells

Proton and carbon beam therapy is currently recognized as the most effective and highly accurate form of radiation therapy for deeply located tumors, including radioresistant ones. This is due to the fact that they have all the advantages of spatial dose distribution and, at the same time, are densely ionizing radiations capable of effectively affecting hypoxic, slow-growing tumors and other neoplasms that are insensitive to traditional types of radiation. It is well known that one of the main methods for treating neoplasms is chemotherapy. The predominant mechanism of action of anti-tumor drugs is the induction of DNA damage with the subsequent impossibility of repair. In our study, we used an anti-tumor antibiotic of the anthracycline series, doxorubicin. The assessment of the potential significance of the synergistic interaction of ionizing radiation with chemical preparations in medical radiology remains an urgent and unresolved problem. It is possible to achieve the maximum effect of the combined action of two agents when they act simultaneously. The phenomenon of synergy can be used to optimize the combined use of radiation and chemotherapy in clinical practice. In this regard, it seems relevant to conduct a study for HeLa cancer cells exposed to ionizing radiation, an antitumor drug, as well as their combination. In the course of the study, results were obtained on the manifestation of the synergistic nature of the agents used, which is of great practical and theoretical importance for understanding the mechanism of the combined effect of ionizing radiation and the chemotherapy drug (doxorubicin). The obtained data can be helpful in optimizing the combined effects in order to achieve maximum synergistic interaction.

Exosomal microRNA-107 reverses chemotherapeutic drug resistance of gastric cancer cells through HMGA2/mTOR/P-gp pathway

Background RNA cargo in exosomes, especially microRNAs (miRNAs), play an important role in the chemotherapy drug resistance of human cancers. However, the role and mechanism of exosomal miR-107 on multidrug resistance of gastric cancer cells was still not clear. In this study, we sought to explore whether exosomal miR-107 could reverse the resistance of gastric cancer cells to the chemotherapy drugs. Methods We extracted exosomes from sensitive (SGC-7901, MGC-803) and resistant (SGC-7901/5-FU) gastric cancer cells by ultracentrifugation and the isolated exosomes were identified using transmission electron microscopy (TEM) and dynamic light scattering analysis (DLS). The expression of miR-107 and high mobility group A2 (HMGA2) were detected by real-time quantitative PCR (RT-qPCR). MTT assay was used to investigate the effect of exosomes on gastric cancer cells growth in vitro. The uptake of exosomes by recipient cells were observed using a fluorescence microscope. The predicted target relationship between miR-107 and HMGA2 was verified by gauss-luciferase reporter assay. The expression of HMGA2, p-mTOR/mTOR, P-gp and other exosomal indicated marker proteins was detected by western blot. Results Our results indicated that the isolated exosomes were typically cup-like lipid bilayer membranes structure. SGC-7901/5-FU cells were cross-resistant to chemotherapy drug cisplatin (CDDP), and the sensitive cells-secreted exosomes drastically reversed the resistance of the resistant GC cells to the chemotherapeutic drugs, which was verified by exosomal inhibitor GW4896. Mechanistically, the reversal effect was mainly mediated by exosome-secreted miR-107 through downregulating the expression of target molecular HMGA2 and inhibiting HMGA2/mTOR/P-gp pathway, which were supported by results from luciferase reporter assay and rescue assay. Conclusions These findings demonstrated that exosome-transmitted miR-107 significantly enhanced the sensitivity of resistant gastric cancer cells to chemotherapeutic agents by mediating the HMGA2/mTOR/P-gp axis and exosomal miR-107 may be a novel target in gastric cancers treatment.

Active Targeting Gold Nanoparticle for Chemotherapy Drug Delivery: A Review

Objective Active targeting strategy in chemotherapy drug delivery aims to improve the therapeutic outcomes and minimise the side effects of chemotherapeutics. This review discusses utilising ligands attached to gold nanoparticles (AuNPs) along with several specific ligands attached to AuNPs for active targeting in chemotherapy drug delivery. Key finding Antibodies, peptides, vitamins, DNA, polysaccharides, aptamers, and hormones showed active-targeting abilities as ligands attached to AuNPs. Active-targeting AuNPs enhanced cellular uptake and cytotoxicity in a specific cancer cell in vitro while reducing tumor growth in vivo by improving the photothermal, photodynamic and chemotherapy effects. Active-targeting ligands increased the internalization of AuNPs loaded onto the specific tumour site and minimised the accumulation in the normal site. Conclusion AuNPs with active-targeting ligands such as antibodies, peptides, vitamins, DNA polysaccharides, aptamers, and hormones can improve the therapeutic outcomes of chemotherapeutics and can attenuate the toxicity effect in normal cells. For further research and development, researchers should be addressing AuNP characterization, drug–ligand disposition, active-targeting AuNP quantification, and target-AuNPs pertinence concerning the desired therapeutic outcomes.

Cancer cell-autonomous cGAS-STING response confers drug resistance

As an evolutionarily conserved DNA-sensing machinery in innate immunity, the cGAS-STING pathway has been reported to play an important role in immune surveillance and tumor suppression. Recent evidence suggests an intriguing tumor- and metastasis-promoting effect of this signaling pathway, either in a cancer cell-autonomous or a cancer cell-nonautonomous, bystander cell-mediated manner. Here, we show a new face of cGAS-STING signaling whose activation in a cancer-cell-autonomous response manner confers drug resistance. Targeted or conventional chemotherapy drug treatment induced cancer cell cytosolic DNA accumulation and triggered subsequent cGAS-STING signaling activation in cancer cell lines and the human cell-derived xenograft tumors. This activation promoted an acquisition and maintenance of drug resistance which was prevented and overcome in vitro and in vivo by blockade of STING signaling. This finding highlights a new face of cGAS-STING signaling and an ability of cancer cells to hijack the evolutionarily conserved inflammatory signaling to counteract drug stress and warrants a caution in combining STING agonist with targeted or conventional chemotherapy drug treatment, a strategy prevailing in current clinical trials.

The immunomodulatory properties of the HDAC6 inhibitor ACY241 supports robust anti-tumor response in NSCLC when coupled with the chemotherapy drug Oxaliplatin

Background: Durable treatments that benefit a wide pool of patients remain elusive for Non-small cell lung cancer (NSCLC). The success of immunotherapy in a subset of NSCLC patients highlights the potential contribution of immune response to anti-tumor immunity while underscoring a need for broadly applicable therapeutic strategies. HDAC inhibitors are a promising class of drugs whose immunomodulatory properties are now being appreciated. In the present study, we evaluated the effects of the HDAC6 inhibitor, ACY241 on lung tumor immune compartment with the goal of understanding the scope of its immunomodulatory properties and its therapeutic potential in combination with Oxaliplatin. Methods: Lung adenocarcinoma-bearing mice were treated with ACY241 or vehicle after which the proportions and phenotype of tumor-associated T cells and macrophages were evaluated by comprehensive flow cytometric analysis. Bulk RNA-sequencing was also conducted on both cellular subsets to interrogate the transcriptomic changes associated with ACY241 treatment relative to vehicle controls. In vivo drug efficacy study was performed by administration of ACY241 and/or Oxaliplatin and assessing tumor growth and survival of tumor-bearing mice. Ex vivo functional studies was performed to assess tumor-associated T cell effector function as it correlates with measured outcomes. Results: We demonstrate that ACY241 promotes increased presence of T and NK cells in the lung tumors of treated mice. The tumor-associated T cells under ACY241 treatment displayed enhanced activation, proliferation, and effector profile. In addition, tumor-associated macrophages exhibited increased expression of MHC and co-stimulatory molecules while expression of inhibitory ligands were reduced. RNA-sequencing of both tumor-associated T cells and macrophages revealed significant genomic changes in both subsets that is consistent with ACY241-mediated enhancement of immune priming. These broad immunomodulatory properties of ACY241 were associated with significantly enhanced tumor-associated T cell effector functionality, robust anti-tumor response, and significantly prolonged survival of NSCLC-bearing mice when combined with the chemotherapy drug Oxaliplatin. Conclusion: Collectively, our studies highlight the broad immunomodulatory effect of ACY241 as a promising HDAC6 inhibitor which coupled with Oxaliplatin promotes robust therapeutic outcomes in a pre-clinical model of NSCLC, providing compelling rationale for the clinical testing of this novel combinatorial regimen in NSCLC.