Synergistic Anticancer Effect Research Articles

Short-course radiotherapy-based total neoadjuvant therapy combined with tislelizumab in the treatment of locally advanced rectal cancer (Neo-STAR): Early outcomes of a prospective, randomized phase II trial.

150 Background: It has been found that radiotherapy possess synergistic anticancer effect with immune checkpoint inhibitors (ICIs). Therefore, this phase II randomized clinical trial (RCT) (ClinicalTrials.gov identifier: NCT05086627) aimed to evaluate the efficacy and safety of SCRT followed by CAPOX and tislelizumab in patients with LARC. Methods: Patients initially diagnosed rectal adenocarcinoma with cT1-2N+M0 or cT3-4NanyM0 were recruited, randomly assigned to receive SCRT (25Gy/5f), followed by four cycles of CAPOX combined with tislelizumab or CAPOX alone, respectively. After total mesorectal excision (TME), two cycles of postoperative adjuvant chemotherapy were given according to the patient's preferences. The pCR rate was set as the primary endpoint, and the major pathological response (MPR) (tumor regression grade (TRG) 0+1), 3-year progression free survival (PFS), 3-year overall survival (OS) and treatment safety were set as the secondary endpoints. R esults: Between September 2021 and March 2024, 118 patients were randomly assigned and 111 patients started allocated treatment, with 53 in the trial group and 58 in the control group. Ninety-six patients (86.5%) completed SCRT and 4 cycles of CAPOX chemotherapy with/without tislelizumab, including 49 patients (92.5%, 49/53) in the trial group and 47 patients (81.0%, 47/58) in the control group. Eighty-two patients (85.4%) had surgical resection, including 42 patients (85.7%, 42/49) in the trial group and 40 patients (85.1%, 40/47) in the control group. Among 82 patients who underwent surgery, 54.8% (23/42) patients in the trial group achieved pCR compared with 37.5% (15/40) in the control group. During the neoadjuvant treatment period, the incidence of grade 3-4 AEs were 9.4% in the trial group and 10.3% in the control group. Conclusions: SCRT-based TNT combined with tislelizumab followed by TME exhibited a favorable pCR rate in LARC. Clinical trial information: NCT05086627 . Surgical and postoperative pathological outcomes. Characteristic Experimental group (n= 42 ) Control group (n=4 0 ) R0 resection Yes 42 (100%) 40 (100%) No 0 (0%) 0 (0%) pCR Yes 23 (54.8%) 15 (37.5%) No 19 (45.2%) 25 (62.5%) TRG score 0 23 (54.8%) 15 (37.5%) 1 3 (7.1%) 2 (5%) 2 14 (33.3%) 15 (37.5%) 3 2 (4.8%) 8 (20%) Pathological T stage T0 24 (57.1%) 15 (37.5%) Tis 1 (2.4%) 0 (0%) T1 0 (0%) 1 (2.5%) T2 9 (21.4%) 6 (15%) T3 6 (14.3%) 10 (25%) T4 2 (4.8%) 8 (20%) Pathological N stage N0 39 (92.9%) 36 (90%) N1 3 (7.5%) 3 (7.5%) N2 0 (0%) 1 (2.5%) Type of surgery Anterior resection 36 (85.7%) 24 (60%) Abdominoperineal resection 6 (14.3%) 13 (32.5%) Hartmann procedure 0 (0%) 3 (7.5%) Anus preservation Yes 36 (85.7%) 27 (67.5%) No 6 (14.3%) 13 (32.5%)

Synergistic anti-cancer effects of piezoelectric hexagonal boron nitride nanocarriers for controlled doxorubicin release.

This study aims to develop a piezoelectric drug delivery system based on hexagonal boron nitride nanosheets (hBNs). hBNs were synthesized using the chemical vapor deposition (CVD) method and characterized through imaging and spectroscopic techniques. Their piezoelectric properties were evaluated to confirm their functionality. Subsequently, the potential of hBNs as nanocarriers was assessed through in vitro experiments with doxorubicin (Dox) as a model drug. The piezoelectric hBNs were successfully synthesized and exhibited efficient loading and controlled release of Dox. In vitro experiments conducted on PC3 (human prostate cancer) and PNT1A (normal adult prostate epithelial) cell lines demonstrated that ultrasound (US)-induced Dox-loaded hBNs (hBN-Dox) significantly inhibited the proliferation of prostate cancer cells, achieving efficacy at a much lower Dox concentration compared to conventional methods. The system enhanced reactive oxygen species (ROS) generation, impaired cancer cell colony formation, and induced both early and late apoptosis. These findings highlight the potential of piezoelectric hBNs as nanocarriers for efficient drug delivery, leveraging the synergistic effect of piezoelectricity-induced drug release and the degradation products of hBNs in biological media. Their ability to enhance drug efficacy while reducing the required dose holds promise for advanced cancer therapies.

Natural Compounds and Histone Deacetylase Inhibitors: A Combined Approach Against mCRPC Cells

Background: Sodium butyrate (NaBu), a short-chain fatty acid, modulates global gene expression through histone deacetylase (HDAC) inhibition, suppressing proliferation and inducing apoptosis in various cancers. Rutin (RUT), a polyphenolic flavonoid found in many plants, exhibits notable anticancer properties. Combining chemotherapeutic agents with natural polyphenols represents a promising strategy for cancer therapy. This study aims to evaluate, for the first time, the potential effects of NaBu and RUT combination therapy on metastatic castration-resistant prostate cancer (mCRPC) cells. Methods: PC-3 cells were treated with varying concentrations of NaBu, RUT, and their combinations. Cell viability was assessed using the WST-1 assay. Based on combination index values, selected treatments were further analyzed for apoptosis (Annexin V assay), intracellular reactive oxygen species (ROS) production, mRNA expression levels, and changes in cell and nuclear morphology. Results: The combined treatment of NaBu and RUT significantly reduced cell viability compared to individual treatments. Enhanced apoptotic induction and elevated ROS levels were observed in combination-treated cells, alongside notable changes in cellular and nuclear morphology and mRNA expression levels. Conclusions: NaBu and RUT combination therapy exhibits a synergistic anticancer effect in mCRPC cells by inhibiting cell viability, inducing apoptosis, and increasing ROS production. These findings suggest a promising therapeutic approach that warrants further investigation to elucidate the underlying molecular mechanisms and assess its potential in preclinical and clinical settings.

Synergistic anticancer effects of cisplatin and phenolic aglycones of the aerial part of Rumex dentatus L. in tongue squamous cell carcinoma: insights from network pharmacology and biological verification

BackgroundOral squamous cell carcinoma (OSCC) ranks as the sixth most common malignancy globally. Cisplatin is the standard chemotherapy for OSCC, but resistance often reduces its efficacy, necessitating new treatments with fewer side effects. Rumex dentatus L., from the Polygonaceae family, is known for its medicinal properties, but its anticancer potential has not been thoroughly explored. This study aimed to investigate the synergy between cisplatin and an extract from the aerial parts of R. dentatus L. in treating tongue carcinoma (HNO97) in vitro, using network pharmacology, biological verification, and phytochemical analysis.MethodsThe study included UPLC-ESI–MS/MS analysis, cytotoxicity assays, cell cycle analysis, apoptosis assessment, and RT-qPCR for gene expression of Bcl2, p53, and ATG7. Potential targets were identified, and mechanisms of action were examined through online databases and enrichment analyses.ResultsThe R. dentatus L. extract contained 14 phenolic aglycons. Combining cisplatin and R. dentatus L. was more effective in inhibiting proliferation, inducing cell cycle arrest and apoptosis, and reducing autophagy in HNO97 cells than cisplatin alone. KEGG analysis indicated that the drug combination might work through pathways like PI3K-Akt signaling, microRNAs in cancer, and EGFR tyrosine kinase inhibitor resistance.ConclusionsCombining cisplatin with R. dentatus L. may be a promising approach for treating tongue carcinoma by affecting multiple pathways, providing a new perspective for developing more effective treatments for OSCC.

Synergistic Anti-Cancer Activities of Curcumin Derivative CU17 Combined with Gemcitabine Against A549 Non-Small-Cell Lung Cancer Cells

Recently, the curcumin derivative CU17 possessing HDAC inhibitory activity has been shown to synergistically enhance the anti-proliferative activity of Gem against lung cancer cells. Nevertheless, the mechanism(s) underlying the synergistic anti-cancer effect remains to be investigated. This study aimed to investigate the mechanisms that underpin the anti-cancer activity of the combined Gem and CU17 against NSCLC A549 cells both in vitro and in mouse xenograft models. CU17 was successfully synthesized and subsequently investigated for its combination effects with Gem on inductions of cell cycle arrest and apoptosis in A549 cells. The combination treatment substantially decreased cell survival through S phase prolongation and G2/M phase cell cycle arrest via up-regulating the expressions of p21 and p53 proteins. Additionally, CU17 potentiated the apoptotic effect of Gem in A549 cells by increasing the Bax/Bcl-2 ratio. The co-treatment resulted in an up-regulation of pERK1/2 and Ac-H3 expression. An in vivo study demonstrated that CU17 significantly improved the anti-cancer effect of Gem in nude mice utilizing A549 cell xenografts. The hematoxylin and eosin (H&E) staining results indicated that CU17 decreased the toxicity of Gem to the liver, kidneys, and spleen. Overall, CU17 enhanced the effectiveness of Gem while decreasing its toxicity. This compound shows promise as a chemosensitizer for NSCLC treatment with Gem.

Assessing the Efficacy of Mitochondria-Accumulating Self-Assembly Peptides in Pancreatic Cancer: An Animal Study.

Although pancreatic cancer presents with one of the most unfavorable prognoses, its treatment options are very limited. Mitochondria-targeting moieties, considered a new and prominent treatment modality, are expected to demonstrate synergistic anticancer effects due to their distinct mechanism compared to conventional chemotherapeutic approaches. This study evaluated the therapeutic potential of mitochondria-accumulating self-assembly peptides, referred to as Mito-FFs, utilizing both in vitro and in vivo pancreatic cancer models. Cellular viability assays revealed a concentration-dependent decrease in the survival of MIA-PACA2 pancreatic cancer cells upon exposure to Mito-FF treatment (p < 0.05). Subsequent in vitro Mito-FF treatments prompted the use of several molecular analyses, including Real-time PCR, Western blot analysis, and MitoSOX staining, which collectively indicated an upsurge in apoptosis, a concurrent reduction in the antioxidant enzyme expression, and an elevation in mitochondrial ROS levels (p < 0.05). In a murine xenograft model of pancreatic cancer, the intravenous administration of Mito-FF yielded a notable reduction in the tumor volume. Moreover, it upregulated the expression of pro-apoptotic markers, such as cleaved PARP and c-caspase 3, while concurrently downregulating the expression of an anti-apoptotic marker, MCL-1, as evidenced by both Western blot analysis and immunohistochemical staining (p < 0.05). It also resulted in the reduced expression of antioxidant enzymes like HO-1, catalase, and SOD2 within excised tumor tissues, as confirmed using Western blot analysis (p < 0.05). Cumulatively, the findings underscore the significant anticancer efficacy of Mito-FF against pancreatic cancer cells, predominantly mediated through the induction of apoptosis, suppression of antioxidant enzyme expression, and enhancement of mitochondrial ROS levels within the tumor microenvironment.

Design, Synthesis, and Anticancer Activity of Drug-like Iron Chelators/G-Quadruplex Binders as Synergic Dual Targeting Agents.

Iron homeostasis is strictly related to numerous physiological pathways including cell cycle progression and cell growth. The newest anticancer strategies focus on either depleting the cells with a suitable chelator or increasing their loading by administering iron complexes to induce ferroptosis. Iron depletion inhibits cell proliferation, while iron overload induces the damage of guanine nucleobases in G-quadruplex structures via ROS generation, leading to genome instability. Here, we demonstrated that designing a molecular chimera embodying structural requirements for both iron chelation and G-quadruplex binding can result in dual-targeting compounds endowed with synergistic anticancer effects. We designed, synthesized, and tested a library of such compounds through biophysical and biological experiments. Compound 16 emerged as a lead candidate and a pharmacological tool able to chelate iron and stabilize G-quadruplexes in human leukemia Jurkat cells. Notably, it also localizes in the cell nucleus, serving as an intrinsically fluorescent nuclear tracer for the labile iron pool.

Identification of the atypical antipsychotic Asenapine as a direct survivin inhibitor with anticancer properties and sensitizing effects to conventional therapies.

Therapy resistance in human cancers is a major limitation in Clinical Oncology. In this regard, overexpression of anti-apoptotic proteins, such as survivin, has been described in several tumors, contributing to this clinical issue. Survivin has a dual role in key cellular functions, inducing cell cycle progression and inhibiting apoptosis; thus, survivin is an attractive target for cancer therapy. Therefore, we focused on identifying and validating a novel specific, directly binding survivin inhibitor for cancer treatment and tumor sensitization to conventional proapoptotic therapies. In this work, we conducted a structure-based high-throughput virtual screening at the survivin homodimerization domain. Asenapine Maleate (AM), an approved drug for central nervous system diseases, was identified as a direct binder of the survivin homodimerization domain and it significantly affected cell viability of lung, colon, and brain cancer cell lines. Direct interaction of AM to survivin protein was corroborated by surface plasmon resonance and a specific survivin protein decrease was observed in cancer cells, compared to other inhibitors of apoptosis proteins. Therapeutic in vivo studies showed an impairment of tumor growth in AM-treated mice. Finally, a synergistic anticancer effect was detected in vitro when combined with different conventional chemotherapies, and in vivo studies showed higher antitumor effects when combined with cisplatin. Altogether, our results identify AM as a specific direct binding inhibitor of survivin, showing anticancer properties in vitro and in vivo and sensitizing effects when combined with cisplatin, opening the possibility of repositioning this approved drug for cancer treatment.

A facile combined therapy of chemotherapeutic agent and microRNA for hepatocellular carcinoma using non-cationic nanogel.

High drug resistance remains a challenge for chemotherapy against hepatocellular carcinoma (HCC). Combining chemotherapeutic agents with microRNA (miRNA), which simultaneously regulates multiple pathways, offers a promising approach to improve therapeutic efficacy against HCC. Although cationic amphiphilic copolymers have been used to co-deliver these agents, their effectiveness is often limited by low co-encapsulation efficiency and inherent cationic toxicity. In this study, we developed a facile approach to co-deliver doxorubicin (DOX) and miRNA-26a (miR-26a) using a non-cationic nanogel. The incorporation of an amphiphilic monomer and a lysosomal enzyme-sensitive crosslinker endows the nanomedicine with several advantages, including high co-encapsulation efficiency, lysosomal escape, and minimal toxicity. miR-26a significantly increased the sensitivity of HCC to DOX by 3.35-fold through targeting multiple pathways, and promoted DOX penetration within tumor tissue through reducing type I collagen content, thereby showing significant synergistic anticancer effects. This study provides a facile and biosafe nanoplatform for the efficient co-delivery of DOX and miRNA with synergistic drug effect.

Perfluorocarbon-polyepinephrine core-shell nanoparticles as a near-infrared light activatable theranostic platform for bimodal imaging-guided photothermal/chemodynamic synergistic cancer therapy.

Background: Activatable multifunctional nanoparticles present considerable advantages in cancer treatment by integrating both diagnostic and therapeutic functionalities into a single platform. These nanoparticles can be precisely engineered to selectively target cancer cells, thereby reducing the risk of damage to healthy tissues. Once localized at the target site, they can be activated by external stimuli such as light, pH changes, or specific enzymes, enabling precise control over the release of therapeutic agents or the initiation of therapeutic effects. Furthermore, these nanoparticles can be designed to incorporate multiple therapeutic modalities, including chemotherapy, photothermal therapy (PTT), and chemodynamic therapy (CDT). This comprehensive approach facilitates real-time monitoring of treatment efficacy and allows for dynamic adjustments to therapy, resulting in more personalized and effective cancer treatments. Methods: This study reports the synthesis of perfluorocarbon (PFC)-encapsulated fluorescent polyepinephrine (PEPP) nanoshells chelated with Fe2+ (PFC@PEPP-Fe) and explores their potential for bimodal imaging and synergistic combination therapy in cancer treatment. The cellular uptake, cytotoxicity, and in vitro therapeutic efficacy of PFC@PEPP-Fe were assessed using 4T1 breast cancer cells. In vivo bimodal imaging using fluorescence (FL) and ultrasound (US) was conducted after injection into 4T1 tumor-bearing balb/c nude mice. The synergistic anticancer effects of PFC@PEPP-Fe, combining CDT and PTT, were evaluated following 808 nm laser irradiation (1 W/cm²) for 5 min, with treatment outcomes monitored over a 14 days period. Results: Both in vitro and in vivo studies demonstrated that PFC@PEPP-Fe enables effective bimodal imaging and exhibits substantial anticancer efficacy through the synergistic effects of PTT and CDT. Near-infrared (NIR) laser irradiation increased the temperature, enhancing the release of O2 and the production of H2O2, which in turn amplified the CDT effect. The combination of PFC@PEPP-Fe administration and NIR laser significantly reduced tumor volume, slowed tumor growth, and improved survival in 4T1 tumor-bearing mice, confirming the strong anticancer activity due to the PTT/CDT synergy. Conclusions: As a multifunctional theranostic nanoparticle, PFC@PEPP-Fe not only enables cancer cell-specific US/FL bimodal imaging through the generation of microbubbles from its PFC core and fluorescent PEPP shells but also facilitates synergistic chemodynamic and photothermal therapeutic actions under NIR laser irradiation, which induces the self-supply of H2O2 and O2 within cancer cells.

Anti-miR21-conjugated DNA nanohydrogel for enhanced cancer therapy.

MicroRNAs (miRNAs) are non-coding, endogenous small single-stranded RNA molecules involved in post-transcriptional regulation of gene expression. It has been demonstrated that dysregulation of miRNA plays a major role in tumor formation, proliferation, and metastasis. Therefore, the delivery of anti-miRNA oligonucleotides to block the activity of these oncogenic miRNAs is a high-potential anti-cancer therapy approach. In particular, miRNA-21 (miR-21) can be an excellent target as it is an oncogenic miRNA that is upregulated in various cancers including glioblastoma, breast cancer, and colon cancer. However, anti-miRNAs are unstable in the physiological environment and have low cell membrane permeability, making it difficult to accumulate at certain concentrations to have anti-cancer effects within cancer cells. To overcome these difficulties, we developed anti-miR-21 functionalized DNA hydrogel (amiR-21 Dgel). We confirmed the improved physiological stability of amiR-21 Dgel in vitro, and observed that it blocked up to 96.6% of miR-21 in HeLa cells, and reduced cell viability down to 77.9% for 72h. In particular, RT-qPCR analysis demonstrated that blocking of miR-21 induces increased mRNA expression of the tumor suppressor genes, PTEN and PDCD4 by 6.23- and 6.87-fold, respectively. In addition, the Dgel can act as a drug delivery vehicle, intercalating anticancer drugs such as doxorubicin (Dox) to be delivered into cells. DOX, an anticancer drug, showed a synergistic anticancer effect with amiR-21, which was delivered together. We expect that this approach will be a convenient to optimization and highly effective strategy for anticancer therapy employing antisense miRNAs.

Synergistic Anti-Cancer Effects of Curcumin and Thymoquinone Against Melanoma.

Combining anti-cancer agents in cancer therapies is becoming increasingly common because of their improved efficacy, reduced toxicity, and decreased risk of resistance development. Melanoma, a highly aggressive form of skin cancer characterized by limited treatment options due to chemoresistance, poses a considerable challenge for effective management. Here, we test the hypothesis that dietary supplements such as thymoquinone (TQ) and curcumin (CU) cooperatively modulate cancer-associated cellular mechanisms to inhibit melanoma progression. Through a series of in vitro experiments utilizing the A375 melanoma cell line, including assessments of cell viability, apoptosis, multicellular tumor spheroid models, reactive oxygen species (ROS) quantification, metabolomics analysis, and RNA sequencing, we established that the combined application of TQ and CU exhibited superior anti-tumor effects compared to their individual use. Our results indicate that the combination treatment significantly inhibited cell viability and induced apoptosis more effectively than either agent alone, with optimal synergy observed at concentrations of 25 µM CU and 10 µM TQ against A375 cells. Additionally, the combination treatment markedly elevated ROS levels, selectively activating the mitochondrial apoptotic pathway via caspase-9. Differential gene expression analysis further revealed a unique synergistic effect of the combination treatment, with enhanced regulation of genes related to oxidative stress and apoptosis. Notably, pathways such as mitochondrial apoptotic signaling and redox homeostasis were more effectively influenced by the combination, with genes such as GPX3, CYP4F11, and HSPB8 cooperatively regulated. Overall, the findings suggest that, in combination, TQ and CU acts synergistically against melanoma; however, further experimental and clinical studies are required to confirm its therapeutic potential.

The Simultaneous Treatment of PC-3 Cells with the DNA-Demethylating Agent Decitabine and S-Adenosylmethionine Leads to Synergistic Anticancer Effects.

Background: Epigenetic dysregulation is a common feature of cancer. Promoter demethylation of tumor-promoting genes and global DNA hypomethylation may trigger tumor progression. Epigenetic changes are unstable; thus, research has focused on detecting remedies that target epigenetic regulators. Previous studies have suggested that concordantly targeting hypomethylation and hypermethylation is beneficial for suppressing both the oncogenic and pro-metastatic functions of cancer cells. Therefore, we aimed to investigate the effect of a combination of S-adenosylmethionine (SAM) and the demethylating agent decitabine on prostate cancer cells. Materials and Methods: Prostate cancer cells (PC-3) were treated with SAM, decitabine, or a combination of both. Proliferation, migration, invasion, and methylation assays were also performed. A transcriptome study was conducted to detect different gene clusters between the treatment groups, followed by analyses using the Kyoto Encyclopedia of Genes and Genomes pathway and ingenuity pathway analysis. Finally, to gain information on differential gene expression, promoter methylation studies were performed. Results: Groups treated with decitabine, SAM, or their combination showed reduced proliferative capacity. The decitabine-treated group showed a marginal increase in cell migration and invasion, whereas the SAM-treated and combination treatment groups showed reduced invasion and migration potential. Methylation assays demonstrated the restoration of decitabine-induced demethylation in prostate cancer samples, whereas the transcriptome study revealed the upregulation of different gene clusters between the treatment groups. Methylation studies confirmed that SAM could restore the decitabine-induced demethylation of proto-oncogenes, but it did not induce the re-methylation of tumor-suppressor genes. Conclusions: Combination treatment with SAM and decitabine had an additive effect and did not nullify each other.

Enhanced Anticancer Efficacy of Alkaline Plasma-Activated Water through Augmented RONS Production.

Despite notable advances in anticancer drug development, their manufacture and use pose environmental and health risks due to toxic byproducts, drug residue contamination, and cytotoxicity to normal cells. Therefore, developing cost-effective anticancer treatments with fewer toxic side effects and higher selectivity is essential to the advancement of highly effective anticancer therapies. Plasma-activated water (PAW) offers a green alternative to conventional chemical treatments as it reverts to water within days. However, the limited duration and dose of reactive oxygen and nitrogen species (RONS) in acidified PAW restrict its clinical deployment and the full understanding of their mechanism. In this study, we propose alkaline PAW as an innovative enhancement of the RONS technology. The alkaline PAW generated markedly superior RONS, with about 10 times higher levels of NO2-, H2O2, and ONOO-/O2•- than acidic PAW. The possible RONS generation pathways in alkaline PAW are analyzed by scavengers. In conventional acidic PAW, 70% of the H2O2 concentration is contributed by •OH but only about 20% in alkaline PAW. ONOO- is mainly formed through the reaction of O2•- with NO in alkaline pH, while in acidic PAW, it mainly forms from NO2- and H2O2. The results unveiled the synergistic and formidable anticancer effects of alkaline PAW against cancer cells, typified by an increase in intracellular ROS/RNS levels. Furthermore, alkaline PAW injection also effectively prevented xenograft tumor growth in mice. We systematically investigated this high-dose anticancer solution without using noble gases, toxic reagents, or extra energy consumption and successfully demonstrated the possibility of alkaline PAW being an effective and environmentally friendly therapeutic technology. The activity is closely linked to the RONS dose, and the generation pathway provides much-needed insight into the fundamental aspects of PAW chemistry required for the optimization of the biochemical activity of PAW.

Synergistic Anti-Cancer Effects of Isocnicin and Radiotherapy in Glioblastoma: A Natural Compound's Potential.

Glioblastoma (GBM) is the most aggressive type of brain tumor in adults. Currently, the only treatments available are surgery, radiotherapy, and chemotherapy based on temozolomide (TMZ); however, the prognosis is dismal. Several natural substances are under investigation for cancer treatment. 8α-O-(3,4-dihydroxy-2-methylenebutanoyloxy) dehydromelitensine (Isocnicin) is a natural compound derived from Centaurea species and was found to exhibit cytostatic/cytotoxic effect against different cell lines. In this study, we investigated the anti-glioma effects of isocnicin in U87 and T98 glioblastoma cell lines, as well as the effects of combined treatment with radiotherapy. Cell viability was evaluated with the trypan blue exclusion assay, cell cycle distribution was examined using flow cytometry, and the effects of the combination treatment were analyzed with CompuSyn software(1.0). The result showed that isocnicin significantly reduced cell viability in U87 and T98 cell lines in a dose-dependent manner and IC50 values were calculated. Administration of isocnicin alone induced both S and G2/M cell cycle arrest in U87 and T98 cells in a dose-dependent manner. Moreover, when cells were treated with increasing concentrations of isocnicin, followed by 2 or 4 Gy of radiation, the percentage distribution of the cells in the G2/M phase was increased considerably in both U87 and T98 cell lines. Here, we show for the first time that co-treatment of isocnicin with radiation exerts a synergistic antiproliferative effect in glioblastoma cell lines. Natural compounds are promising for glioblastoma treatment. Further studies will be necessary to unravel isocnicin's mechanism of action and its synergistic effect with radiation on glioblastoma treatment.

Hybrid Nanoparticle for Co-delivering Paclitaxel and Dihydroartemisinin to Exhibit Synergic Anticancer Therapeutics.

Anticancer treatment is required to provide effective and safe patient medicines. This research aided in developing and applying nanoparticles (NPs) for cancer treatment. The poor solubility of paclitaxel (PTX) restricts its therapeutic efficacy because of allergic side effects caused by formulation excipients. To overcome this, PTX was coupled with artemisinin derivatives and loaded into an NP drug delivery system to enhance its effects while addressing its low solubility. This study prepared and characterized a hybrid PLGA-lecithin NP containing dihydroartemisinin (DHA) and PTX for synergic anticancer therapy. A lyophilization study improved the stability of the NP drug formulations. Dual PTX- and DHA-loaded PLGA- and lecithin-based NPs were prepared using a single-step solvent evaporation method. The NP suspensions were lyophilized, and the types and ratios of cryoprotectants were investigated. The physicochemical properties of NPs and lyophilized cakes (Lyo-NPs) were characterized. The stability of the Lyo-NPs was investigated at 2-8°C and room conditions. The anticancer effects of the drug combination, NP suspension, and lyophilized powder were analyzed using an in vitro cytotoxicity assay and an in vivo model. The optimal PTX-DHA loaded PLGA-lecithin-NP was formulated (200 nm, PDI: 0.248 ± 0.003, Zeta potential: -33.60 ± 3.39 mV). Mannitol was selected for lyophilization. Lyo-NPs improved the stability of the NPs (1 year), wherein the physicochemical properties of the NPs were maintained (RDI was close to 1.0). An in-vitro cytotoxicity assay of PTX combined with DHA showed a synergistic anticancer effect (CI <1.0). The suppressive effects of Lyo-NPs on tumor growth in vivo were dose-dependent. While the cocktail of free drugs showed high toxicity (7.5 mg PTX-15 mg DHA/kg) in-vivo, Lyo-NPs showed no statistical differences in hematological and biochemical parameters compared to the control. Dual-drug-loaded hybrid PLGA-lecithin NP is a potential system to minimize severe side effects while enhancing antitumor efficacy, in which lyophilization is a key process to increase stability.

MRTX1719, an MTA-cooperative PRMT5 Inhibitor, Induces Cell Cycle Arrest and Synergizes With Oxaliplatin and Gemcitabine for Enhanced Anticancer Effects.

MRTX1719 is a novel protein arginine methyltransferase 5 (PRMT5) inhibitor that targets the PRMT5-5'-Methylthioadenosine (MTA) complex called MTA-cooperative PRMT5 inhibitor. MRTX1719 acts specifically on methylthioadenosine phosphorylase (MTAP)-deficient cancer cells; however, its mechanism of action remains unclear. This study aimed to clarify the effects of MRTX1719 on the cell cycle and its synergistic effects with other anticancer drugs. A cell cycle assay was conducted using fluorescence-activated cell sorting to examine the correlation between PRMT5 activity and cells in the G0/G1 phase. The synergistic effects of MRTX1719 and anticancer drugs were evaluated using the Combination Index (CI) and Bliss synergy score (BSS). The synergistic effect was also evaluated by knocking down the endogenous expression of MTAP in HCT116 cells with high MTAP expression. The cell cycle assay showed that the population of cells with reduced PRMT5 activity increased, and the administration of MRTX1719, an MTAP inhibitor, increased the population of cells in the G0/G1 phase. In the synergistic effect assay, oxaliplatin and gemcitabine demonstrated a CI <1 and a BSS >0, indicating a synergistic effect when administered alongside MRTX1719. MTAP knockdown also resulted in <1 in CI and >0 in BSS after the administration of oxaliplatin or gemcitabine with MRTX1719. MRTX1719 reduces PRMT5 activity, leading to cell cycle arrest by increasing the proportion of cells in the G0/G1 phase. Moreover, MRTX1719 exhibits synergistic anticancer effects with oxaliplatin and gemcitabine in MTAP-deficient cancer cells.

Anti-cancer effect of sodium pentaborate in combination with cisplatin on lung cancer cell lines.

Despite the development of novel therapeutic modalities, lung cancer persists as the leading cause of cancer-related mortality. Platinum-based treatments represent the most prominent treatment option, with cisplatin being the most frequently utilized chemotherapeutic agent. However, cisplatin has several serious side effects. A substantial body of evidence has emerged in recent years indicating that boron compounds exhibit anti-cancer properties when administered as monotherapy or in combination with chemotherapy agents. The objective of this study is to examine the anti-cancer effects of Cisplatin (Cis) and sodium pentaborate pentahydrate (NaB), both individually and in combination, on non-small cell lung cancer (NSCLC) cell line A-549 cells and small cell lung cancer (SCLC) cell line DMS-114 cells under in vitro conditions. The effects of cisplatin and NAB on cell survival, apoptosis, the cell cycle, and the expression levels of apoptotic, anti-apoptotic, and tumor suppressor genes were determined by an MTS assay, an Annexin-V assay, a cell cycle analysis, and real-time PCR (qPCR). It was found that the IC-50 value of cisplatin, which was 10 µM when used alone, decreased to 2.5 µM when combined with a non-toxic dose of NaB on the A-549 cell line. BAX and TP53 gene expression levels were elevated by the Nab-Cisplatin combination in the A-549 cell line. The combination was observed to result in an approximately 19-fold increase in CDK2 gene expression in the A-549 cell line and an approximately 6-fold increase in the DMS-114 line, which resulted in S phase and/or G2 phase arrest on the cell cycle. Gene expression levels of Survivin and Ki-67 were decreased by the combination on both cell lines when compared with cisplatin alone. The findings demonstrate that NaB exerts an anti-cancer effect on the A-549 and DMS-114 cell lines. Moreover, when combined with cisplatin, it produces a synergistic anti-cancer effect on the A-549 cell line, whereby apoptosis is activated and cell proliferation is inhibited. The combination of NaB and cisplatin represents a novel approach to the treatment of NSCLC. This is due to the fact that it reduces the IC-50 value of cisplatin and also results in a greater inhibition of cell division and a stronger induction of cell death when used in the context of a combined treatment. Further insight into the effects of the NaB-cisplatin combination will be gained from in vivo experiments and clinical studies.

Macrophage biomimetic intelligent hollow MnO2 nanoparticle for synergistic sonodynamic-immunotherapy of glioblastoma by crossing blood brain barrier

Though emerging novel theranostics based intelligent nanomaterials for cancers are promising ways to solve the disadvantages of traditional therapeutic methods, poor targeting of these nanomaterials and the presence of blood–brain barrier (BBB) in glioblastoma (GBM) seriously reduces the efficacy of GBM treatment. Herein, an intelligent nanoparticle consisting of macrophage membrane coated hollow manganese dioxide loading ce6 (MM-HMnO2@Ce6) was prepared, which could be used for magnetic resonance imaging (MRI) guided sonodynamic therapy (SDT)-immunotherapy of in situ GBM. Comparing to early reports, MM-HMnO2@Ce6 could target intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) receptors on endothelial cells of GBM, and cross BBB, which enhanced the efficiency of GBM treatment. What’s more, the as-prepared nanoparticle also monitored the process of targeting and crossing BBB by MRI due to its tumour microenvironment (TME) responsive feature. What’s more, the detailed therapeutic mechanisms were also determined to be by generating reactive oxygen species (ROS), activating immature DCs and activating the cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway. Overall, this work showcases a remarkable synergistic anticancer effect of SDT-immunotherapy, and also proposes new avenues for research in utilizing MnO2 nanomaterials for GBM treatment.

Synergistic anticancer effects of interleukin-21 combined with therapeutic peptides in multiple cancer cells.

Interleukin-21 (IL-21) is a cytokine produced by various cell types, including T cells, natural killer cells, myeloid cells, and B cells, and has a broad range of potential applications in cancer therapy. To improve the therapeutic index, we explored the use of fusion technologies that involved linking other anticancer peptides to the IL-21 gene using specific linkers. This study aimed to compare the anticancer potential of IL-21 and IL-21 fusion proteins. Antimicrobial peptides possessing anticancer properties were fused with IL-21 gene using a flexible linker (-GGGGS-), and the resulting construct was inserted into the pSecTag2a mammalian expression vector. The cassette was transfected into several cancer cell lines including H1 HeLa, HepG2, MCF-7, MDA-MB-231, HCT-116, HCC-1954, HEK-293, and SF-767. The cytotoxic effects of IL-21 and fusion proteins were evaluated using MTT, Caspase-3, LDH, and scratch assays. The IL-21-Tachyplesin I fusion protein had the strongest antiproliferative activity against all tested cancer cells, followed by IL21-LPSBD2 and IL-21. In contrast, IL21-Cop A3, IL21-CSP I-Plus, and IL21-RGD Temporin-Las did not inhibit the viability of cancer cells. Fusion technology is a promising therapeutic technique that can be used to enhance the cytotoxicity and antiproliferative activity of anticancer proteins such as IL-21.