Synergistic Anticancer Effect Research Articles

Synergistic anticancer effects of metformin and Achillea vermicularis Trin-loaded nanofibers on human pancreatic cancer cell line: An in vitro study

Treatment options for pancreatic cancer are limited and not effective enough despite recent advances in chemotherapy. In this study, Metformin (Met)/Achillea vermicularis Trin. (AV)-loaded polylactic acid (PLA)/polycaprolactone (PCL) nanofibers (NFs) were fabricated by electrospinning and their chemical, mechanical, degradation, thermal, drug release behaviour and kinetic, and morphological properties were characterized. Met/AV-loaded NFs were found more effective against insulinoma cells in vitro than Met-loaded and AV-loaded NFs. Lactate dehydrogenase (LDH) leakage was remarkably higher in Met/AV-loaded NF-treated cells (on day 1 is 50.14% and on day 7 is 46.59%) than in pure NF-treated cells. The density of live cells was lower on the surface of Met/AV-loaded NF compared to Met-loaded and AV-loaded NFs. Met/AV-loaded NF demonstrated a higher apoptosis-inducing effect on insulinoma cells than single drug-loaded NFs according to DAPI nuclear staining. The combination of Met and AV in PLA/PCL NFs could be a novel and effective therapy against pancreatic cancer via a local application.

Research advances in nanomedicine applied to the systemic treatment of colorectal cancer.

The systematic treatment of colorectal cancer (CRC) still has room for improvement. The efficacy of chemotherapy, that of anti-vascular therapy, and that of immunotherapy have been unsatisfactory. In recent years, nanomaterials have been used as carriers to improve the bioavailability of anticancer drugs. For the treatment of colorectal cancer, nanodrugs increase the possibility of more precise targeted delivery. However, the actual benefits may cover more aspects. Nanocarriers can produce synergistic effects with anticancer drugs, including the scavenging of reactive oxygen species and co-delivery of a variety of drugs. Currently, immunotherapy has very limited clinical applications in CRC. Modified nanocarriers can activate the immune microenvironment, which can be used for staging antigen recognition or the immune response. Cancer vaccines based on nanomaterials and modified immune checkpoint inhibitors have shown therapeutic potential in animal models. Considering the direct or indirect relationship between the intestinal microflora and CRC, a variety of nanodrugs that regulate microbial function have been explored as an anticancer strategy, and the special structure of microorganisms can also be used as a basis for improving the delivery of traditional nanoparticles (NPs). This review summarizes recent research performed on nanocarriers in in vivo and in vitro models and the synergistic anticancer effects of nanocarriers, focusing on the interaction between NPs and the body, resulting in enhanced efficacy and immune activation. Furthermore, this review describes the current trend of NPs used in the treatment of CRC.

THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours

BackgroundGastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract and are characterized by activating mutations of c-KIT or PDGFRa receptor tyrosine kinases (RTKs). Despite the clinical success of tyrosine kinase inhibitors (TKIs), more than half of GIST patients develop resistance due to a second mutation. Cyclin-dependent kinase 7 (CDK7) is the catalytic subunit of CDK-activating kinase (CAK), and it plays an important role in the regulation of cell cycle transitions and gene transcription. THZ1, a CDK7 inhibitor, exhibits a dose-dependent inhibitory effect in various cancers.MethodsData from the public GEO database and tissue microarray were used to analyse the gene expression levels of CDKs in GISTs. The impact of CDK7 knockdown and the CDK7 inhibitor THZ1 on GIST progression was investigated in vitro using CCK-8, colony formation, and flow cytometry assays and in vivo using a xenograft mouse model. RNA sequencing was performed to investigate the mechanism of GIST cell viability impairment mediated by THZ1 treatment.ResultsOur study demonstrated that CDK7 is relatively overexpressed in high-risk GISTs and predicts a poor outcome. A low concentration of THZ1 exhibited a pronounced antineoplastic effect in GIST cells in vivo and in vitro. Moreover, THZ1 exerted synergistic anticancer effects with imatinib. THZ1 treatment resulted in transcriptional modulation by inhibiting the phosphorylation of Ser2, Ser5, and Ser7 within RNA polymerase II (RNAPII). c-KIT, an oncogene driver of GIST, was transcriptionally repressed by THZ1 treatment or CDK7 knockdown. Transcriptome sequencing analysis showed that OSR1 acts as a downstream target of CDK7 and regulates c-KIT expression. Taken together, our results highlight elevated CDK7 expression as a predictor of poor outcome in GIST and present the combination of CDK7 and RTK inhibitors as a potent therapeutic strategy to improve the efficacy of GIST treatment.3dK7zp1xpFMvfXo5mnDRH-Video abstract

The Role of Protein Arginine Methyltransferases in DNA Damage Response.

In response to DNA damage, cells have developed a sophisticated signaling pathway, consisting of DNA damage sensors, transducers, and effectors, to ensure efficient and proper repair of damaged DNA. During this process, posttranslational modifications (PTMs) are central events that modulate the recruitment, dissociation, and activation of DNA repair proteins at damage sites. Emerging evidence reveals that protein arginine methylation is one of the common PTMs and plays critical roles in DNA damage response. Protein arginine methyltransferases (PRMTs) either directly methylate DNA repair proteins or deposit methylation marks on histones to regulate their transcription, RNA splicing, protein stability, interaction with partners, enzymatic activities, and localization. In this review, we summarize the substrates and roles of each PRMTs in DNA damage response and discuss the synergistic anticancer effects of PRMTs and DNA damage pathway inhibitors, providing insight into the significance of arginine methylation in the maintenance of genome integrity and cancer therapies.

HDAC6: A unique HDAC family member as a cancer target.

HDAC6, a structurally and functionally distinct member of the HDAC family, is an integral part of multiple cellular functions such as cell proliferation, apoptosis, senescence, DNA damage and genomic stability, all of which when deregulated contribute to carcinogenesis. Among several HDAC family members known so far, HDAC6 holds a unique position. It differs from the other HDAC family members not only in terms of its subcellular localization, but also in terms of its substrate repertoire and hence cellular functions. Recent findings have considerably expanded the research related to the substrate pool, biological functions and regulation of HDAC6. Studies in HDAC6 knockout mice highlighted the importance of HDAC6 as a cell survival player in stressful situations, making it an important anticancer target. There is ample evidence stressing the importance of HDAC6 as an anti-cancer synergistic partner of many chemotherapeutic drugs. HDAC6 inhibitors have been found to enhance the effectiveness of conventional chemotherapeutic drugs such as DNA damaging agents, proteasome inhibitors and microtubule inhibitors, thereby highlighting the importance of combination therapies involving HDAC6 inhibitors and other anti-cancer agents. Here, we present a review on HDAC6 with emphasis on its role as a critical regulator of specific physiological cellular pathways which when deregulated contribute to tumorigenesis, thereby highlighting the importance of HDAC6 inhibitors as important anticancer agents alone and in combination with other chemotherapeutic drugs. We also discuss the synergistic anticancer effect of combination therapies of HDAC6 inhibitors with conventional chemotherapeutic drugs.

Synergistic anticancer effects of curcumin and crocin on human colorectal cancer cells.

Curcumin, a polyphenol compound derived from the Curcuma longa L, and crocin, a hydrophilic carotenoid from Crocus Sativus Linnaeus, are traditionally used in food preparations in many countries and could act as chemopreventive compounds against several diseases, including cancer. In this study, the synergistic effect of curcumin and crocin was investigated for the first time on inducing apoptosis and suppressing colorectal cancer cells (SW-480 cell line). MTT, Annexin V-FITC/PI, and DAPI staining tests were employed to evaluate cell viability and apoptosis induction, respectively. The combined effect of curcumin and crocin on the expression of genes involved in apoptosis and proliferation was quantified using real-time PCR. The combination therapy effect on cell cycle progression was also evaluated by flow cytometry. Based on the obtained results, curcumin and crocin treatment could cooperatively reduce cell viability and induce apoptosis in SW-480 cells by modulating the expression of Bax, Bcl-2, Caspase-3, Caspase-8, Caspase-9, Jak2, Stat3, and Akt1 genes. Besides, curcumin and crocin were able to synergistically increase the cell cycle arrest at the sub G1 phase, induce autophagy and decrease the clonogenic ability of SW-480 cells. These results suggested that curcumin and crocin combination could be considered a more effective therapeutic strategy for inhibiting colorectal cancer.

HDAC8-Selective Inhibition by PCI-34051 Enhances the Anticancer Effects of ACY-241 in Ovarian Cancer Cells.

HDAC6 is overexpressed in ovarian cancer and is known to be correlated with tumorigenesis. Accordingly, ACY-241, a selective HDAC6 inhibitor, is currently under clinical trial and has been tested in combination with various drugs. HDAC8, another member of the HDAC family, has recently gained attention as a novel target for cancer therapy. Here, we evaluated the synergistic anticancer effects of PCI-34051 and ACY-241 in ovarian cancer. Among various ovarian cancer cells, PCI-34051 effectively suppresses cell proliferation in wild-type p53 ovarian cancer cells compared with mutant p53 ovarian cancer cells. In ovarian cancer cells harboring wild-type p53, PCI-34051 in combination with ACY-241 synergistically represses cell proliferation, enhances apoptosis, and suppresses cell migration. The expression of pro-apoptotic proteins is synergistically upregulated, whereas the expressions of anti-apoptotic proteins and metastasis-associated proteins are significantly downregulated in combination treatment. Furthermore, the level of acetyl-p53 at K381 is synergistically upregulated upon combination treatment. Overall, co-inhibition of HDAC6 and HDAC8 through selective inhibitors synergistically suppresses cancer cell proliferation and metastasis in p53 wild-type ovarian cancer cells. These results suggest a novel approach to treating ovarian cancer patients and the therapeutic potential in developing HDAC6/8 dual inhibitors.

The Efficacy and Mechanism of Proteasome Inhibitors in Solid Tumor Treatment.

The ubiquitin-proteasome system (UPS) is critical in cellular protein degradation and widely involved in the regulations of cancer hallmarks. Targeting the UPS pathway has emerged as a promising novel treatment in hematological malignancies and solid tumors. This review mainly focuses on the preclinical results of proteasome inhibitors in solid tumors. We analyzed the published articles associated with the anticancer results of proteasome inhibitors alone or combination chemotherapy in solid tumors. Important data presented in abstract form were also discussed in this review. Proteasome inhibitors, such as bortezomib and carfilzomib, are highly effective in treating solid tumors. The anticancer efficacy is not limited to affect the proteasomal inhibition- associated signaling pathways but also widely involves the signaling pathways related to cell cycle, apoptosis, and epithelial-mesenchymal transition (EMT). In addition, proteasome inhibitors overcome the conventional chemo-resistance of standard chemotherapeutics by inhibiting signaling pathways, such as NF-κB or PI3K/Akt. Combination chemotherapy of proteasome inhibitors and standard chemotherapeutics are widely investigated in multiple relapsed or chemo-resistant solid tumor types, such as breast cancer and pancreatic cancer. The proteasome inhibitors re-sensitize the standard chemotherapeutic regimens and induce synergistic anticancer effects. The development of novel proteasome inhibitors and delivery systems also improves the proteasome inhibitors' anticancer efficacy in solid tumors. This review summarizes the current preclinical results of proteasome inhibitors in solid tumors and reveals the potential anticancer mechanisms.

Computational Exploration of the Synergistic Anticancer Effect of a Multi-Action Ru(II)-Pt(IV) Conjugate.

An in-depth computational study of the ability of a recently proposed multi-action Ru(II)–Pt(IV) conjugate to act as a photosensitizer in photodynamic therapy (PDT) and chemotherapeutic drugs is presented here. The investigated complex is characterized by a polypyridyl Ru(II) chromophore linked to a Pt(IV) complex that, acting as a prodrug, should be activated by reduction releasing the Ru-based chromophore that can absorb light of proper wavelength to be used in PDT. The reaction mechanism for active species formation has been fully elucidated by means of density functional theory and its time-dependent extension. The reduction mechanism, assisted by ascorbate, of the Pt(IV) prodrug to the Pt(II) active species has been explored, taking into consideration all the possible modes of attack of the reductant for releasing the axial ligands and affording active cisplatin. Given the similarity in the photophysical properties of the chromophore linked or not to the Pt(IV) complex, both the Ru(II)–Pt(IV) conjugate precursor and the Ru(II) chromophore should be able to act as PDT photosensitizers according to type I and type II photoprocesses. In particular, they are able to generate singlet oxygen cytotoxic species as well as auto-ionize to form highly reactive O2–• species.

Matairesinol Induces Mitochondrial Dysfunction and Exerts Synergistic Anticancer Effects with 5-Fluorouracil in Pancreatic Cancer Cells.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of cancer and exhibits a devastating 5-year survival rate. The most recent procedure for the treatment of PDAC is a combination of several conventional chemotherapeutic agents, termed FOLFIRINOX, that includes irinotecan, leucovorin, oxaliplatin, and 5-fluorouracil (5-FU). However, ongoing treatment using these agents is challenging due to their severe side effects and limitations on the range of patients available for PDAC. Therefore, safer and more innovative anticancer agents must be developed. The anticarcinoma activity of matairesinol that can be extracted from seagrass has been reported in various types of cancer, including prostate, breast, cervical, and pancreatic cancer. However, the molecular mechanism of effective anticancer activity of matairesinol against pancreatic cancer remains unclear. In the present study, we confirmed the inhibition of cell proliferation and progression induced by matairesinol in representative human pancreatic cancer cell lines (MIA PaCa-2 and PANC-1). Additionally, matairesinol triggers apoptosis and causes mitochondrial impairment as evidenced by the depolarization of the mitochondrial membrane, disruption of calcium, and suppression of cell migration and related intracellular signaling pathways. Finally, matairesinol exerts a synergistic effect with 5-FU, a standard anticancer agent for PDAC. These results demonstrate the therapeutic potential of matairesinol in the treatment of PDAC.

Targeted co-delivery of doxorubicin and methotrexate to breast cancer cells by a pH-sensitive biocompatible polymeric system based on β-cyclodextrin crosslinked glycodendrimer with magnetic ZnO core

Nowadays, co-delivery of multiple therapeutics and combinational therapies using a delivery system is a promising approach to attain a synergistic anticancer effect. Hence, in the present study, we designed and synthesized a new pH-sensitive and biocompatible glycodendrimer immobilized on ZnO coated magnetic nanocomposite (Fe3O4@ZnO@CAMAD-β-CD) with antioxidant properties for co-delivery of doxorubicin (DOX) and methotrexate (MTX) to breast cancer cells. The structural properties of the new synthesized system were analyzed using various techniques. The drug loading results revealed that the Fe3O4@ZnO@CAMAD-β-CD nanocomposite displayed encapsulation efficiency (EE) of 96.08 % for DOX and 68.03 % for MTX. In vitro drug release study at pHs 5, 6.8, and 7.4 also showed that the release process was noticeably controlled, and pH-dependent manner with tumor target release behavior. Furthermore, the results of MTT cytotoxicity assessment, DAPI staining, confocal microscopy, and flow cytometry analysis against MDA-MB-231 breast cancer cell lines illustrated that the prepared Fe3O4@ZnO@CAMAD-β-CD has good biocompatibility and could easily enter the cells. The flow-cytometry analysis also showed that the apoptotic effects of DOX-MTX- Fe3O4@ZnO@CAMAD-β-CD have higher due to the synergistic effect in comparison to free drugs. The DPPH test for the study of antioxidant activity of Fe3O4@ZnO@CAMAD-β-CD nanocomposite showed that the carrier has excellent antioxidant activity (81.3 %). According to the results of this study, the prepared Fe3O4@ZnO@CAMAD-β-CD as a biocompatible carrier could be successfully used in the targeted co-delivery of DOX and MTX to cancer cells.

One-Pot Synthesis of Ag/Quaternary Ammonium Salt Co-Decorated Mesoporous Silica Nanoparticles for Synergistic Treatment of Cancer and Bacterial Infections.

Developing drug delivery nanosystems with both anticancer and antibacterial effects is of great clinical value. Herein, we report a facile approach to synthesize Ag and quaternary ammonium salt (QAS) co-decorated mesoporous silica nanoparticles (MSNs), namely, Ag/QAS-MSNs, for synergistic treatment of cancer and bacterial infections. In vitro studies demonstrated that Ag/QAS-MSNs not only had a strong antibacterial activity against the bacterial pathogens but also could efficiently induce cancer cell death through an apoptotic pathway. Moreover, in vivo combination therapy with Ag and QAS in Ag/QAS-MSNs was also tested in a nude mouse tumor model, and a significant synergistic anticancer effect, which is superior to that obtained by therapy with Ag-MSNs or QAS-MSNs alone, was achieved. Such excellent anticancer and antibacterial activity of Ag/QAS-MSNs could be attributed to the synergistic effect of Ag ions and QAS. Thus, Ag/QAS-MSNs have a promising future as potent anticancer agents with high antibacterial performance.

Solid Self-Nano Emulsifying Nanoplatform Loaded with Tamoxifen and Resveratrol for Treatment of Breast Cancer.

The solid self-nanoemulsifying drug delivery system (s-SNEDDS) is a growing platform for the delivery of drugs via oral route. In the present work, tamoxifen (TAM) was loaded in SNEDDS with resveratrol (RES), which is a potent chemotherapeutic, antioxidant, anti-inflammatory and P-gp inhibitor for enhancing bioavailability and to obtain synergistic anti-cancer effect against breast cancer. SNEDDS were developed using capmul MCM as oil, Tween 80 as surfactant and transcutol-HP as co-surfactant and optimized by central composite rotatable design. Neusilin US2 concentration was optimized for adsorption of liquid SNEDDS to prepare s-SNEDDS. The developed formulation was characterized and investigated for various in vitro and cell line comparative studies. Optimized TAM-RES-s-SNEDDS showed spherical droplets of a size less than 200 nm. In all in vitro studies, TAM-RES-s-SNEDDS showed significantly improved (p ˂ 0.05) release and permeation across the dialysis membrane and intestinal lumen. Moreover, TAM-RES-s-SNEDDS possessed significantly greater therapeutic efficacy (p < 0.05) and better internalization on the MCF-7 cell line as compared to the conventional formulation. Additionally, oral bioavailability of TAM from SNEDDS was 1.63 folds significantly higher (p < 0.05) than that of combination suspension and 4.16 folds significantly higher (p < 0.05) than TAM suspension. Thus, findings suggest that TAM- RES-s-SNEDDS can be the future delivery system that potentially delivers both drugs to cancer cells for better treatment.

Co-Delivery of erlotinib and resveratrol via nanostructured lipid Carriers: A synergistically promising approach for cell proliferation prevention and ROS-Mediated apoptosis activation

Cancer treatments are always associated with various challenges, and scientists are constantly trying to find new therapies and methods. Erlotinib (ELT) is a well-known medicine against non-small cell lung cancer (NSCLC). However, treatments by ELT disrupt therapy due to drug resistance and pose severe challenges to patients. To achieve high-performance treatment, we gained nanostructured lipid carriers (NLCs) to evaluate synergistic anticancer effects of co-delivery of ELT and resveratrol (RES), a natural herbal derived phenol against NSCLC. NLCs are prepared via the hot homogenization method and characterized. In vitro cytotoxicity of formulations were evaluated on adenocarcinoma human alveolar basal epithelial (A549) cells. Prepared NLCs showed a narrow particle size (97.52 ± 17.14 nm), negative zeta potential (-7.67 ± 4.55 mV), and high encapsulation efficiency (EE%) was measured for the prepared co-delivery system (EE% 89.5 ± 5.16 % for ELT and 90.1 ± 6.61 % for RES). In vitro outcomes from cell viability study (12.63 % after 48 h of treatment), apoptosis assay (85.50%.), cell cycle (40.00% arrest in G2-M), and western blotting investigations (decreasing of protein expression levels of survivin, Bcl-2, P-Caspase 3P-caspase 9, and P-ERK 1/2, and additionally, increasing protein levels of BAX, P53, C-Caspase 3 and 9), DAPI staining, and colony formation assays showed the augment cytotoxic performances for co-delivery of ELT and RES loaded NLCs. Our study introduced the co-delivery of ELT and RES by NLCs as a novel strategy to elevate the efficacy of chemotherapeutics for NSCLC.

Pentagalloyl Glucose and Cisplatin Combination Treatment Exhibits a Synergistic Anticancer Effect in 2D and 3D Models of Head and Neck Carcinoma.

Although cisplatin is a first-line chemotherapy drug for head and neck squamous cell carcinoma (HNSCC), its therapeutic efficacy is limited owing to serious side effects and acquired drug resistance. This study determined whether combining pentagalloyl glucose (PGG) and cisplatin enhanced their anti-tumor activities on HNSCC cell lines. We investigated the anticancer effect of PGG combined with cisplatin in 2D and 3D multicellular spheroid cell culture. The results revealed that PGG combined with cisplatin inhibited cell viability and produced synergistic effects. PGG potentiates the anticancer effect of cisplatin by promoting apoptosis and inhibiting cell migration. The western blot and molecular docking analysis revealed that the synergistic effect of the combination treatment may be related to the PGG-mediated reduced expression of phosphorylated STAT3 and phosphorylated Akt. Furthermore, we found that the combined treatment of PGG and cisplatin’s effect on 3D multicellular spheroid size was more potent than the monotherapies. Our findings indicated that the combination therapy of PGG and cisplatin synergistically inhibited HNSCC cancer cell viability and induced apoptosis in 2D and 3D models. The present results suggested that PGG may be a promising adjunct drug used with cisplatin for a practical therapeutic approach to head and neck cancer.

Molecular dynamics simulation and in vitro evaluation of herb-drug interactions involving dietary polyphenols and CDK inhibitors in breast cancer chemotherapy.

Dietary polyphenols such as quercetin and curcumin have been extensively administered to patients with cancer in the form of herbal supplements. They may have a synergistic anticancer effect; however, a risk of pharmacokinetic interactions with selective CDK-4/6 inhibitors that are metabolized by the CYP3A4 enzyme exists. Considering these pharmacokinetic aspects, the current study examined the effects of curcumin and quercetin on human CYP3A4 to ascertain CYP3A4-mediated herb-drug interactions with CDK inhibitors. In this study, using in silico methods and CYP3A4 inhibition kinetics in human liver microsomes and recombinant CYP3A4 enzymes, the effects of concentration-dependent inhibition of CYP3A4 by quercetin and curcumin on CDK inhibitors metabolism were examined. Based on our in-silico docking findings, curcumin and quercetin were considerably bound to CYP3A4 protein and displace CDK inhibitors from the CYP3A4 substrate binding domain. The IC50 values of curcumin and quercetin were 16.10 and 0.05 μM, respectively, for CYP3A4-mediated 1'-hydroxylation of midazolam. The dietary polyphenols prolonged the in vitro half-life of palbociclib and ribociclib by 6.4-fold and decreased their intrinsic microsomal clearance by approximately 4.6 times. Our findings indicate that curcumin and quercetin effectively cause herb-drug interactions and should be cautiously used to avoid therapeutic failure.

Visualizing Lysosomal Positioning with a Fluorescent Probe Reveals a New Synergistic Anticancer Effect

The observation and discovery of lysosome dynamic alterations will greatly contribute to the in-depth understanding of lysosome biology and the development of new cancer therapeutics. To visualize lysosomal dynamics, here we have developed a lysosome-targetable fluorescent probe of NIM-3 showing integrated high selectivity, high photostability, and low cytotoxicity. With the aid of the excellent spatial and temporal imaging capability of NIM-3, three different types of motion of lysosomes were defined, and perinuclear accumulation of lysosomes in response to the pro-inflammatory cytokine stimulus was observed in various cells. More importantly, through lysosomal positioning studies, a new and potential anticancer therapy, i.e., the combination treatment of TNFα (tumor necrosis factor alpha) and chloroquine (CQ, a lysosomal pH elevator), was disclosed. The efficacy of the "CQ + TNFα" treatment was verified by different types of human cancer cells, and the anticancer mechanism may be partially attributed to lysosomal dilation.

Co-Delivery of Repurposing Itraconazole and VEGF siRNA by Composite Nanoparticulate System for Collaborative Anti-Angiogenesis and Anti-Tumor Efficacy against Breast Cancer

Combinations of two different therapeutic modalities of VEGF inhibitors against angiogenesis can cooperatively impede breast cancer tumor growth and enhance therapeutic efficacy. Itraconazole (ITZ) is a conventional antifungal drug with high safety; however, it has been repurposed to be a multi target anti-angiogenesis agent for cancer therapy in recent years. In the present study, composite nanoparticles co-loaded with ITZ and VEGF siRNA were prepared in order to investigate their anti-angiogenesis efficacy and synergistic anticancer effect against breast cancer. The nanoparticles had a suitable particle size (117.9 ± 10.3 nm) and weak positive surface charge (6.69 ± 2.46 mV), as well as good stability and drug release profile in vitro. Moreover, the nanoparticles successfully escaped from endosomes and realized cell apoptosis and cell proliferation inhibition in vitro. In vitro and in vivo experiments showed that the nanoparticles could induce the silencing of VEGF-related expressions as well as anti-angiogenesis efficacy, and the co-loaded ITZ-VEGF siRNA NPs could inhibit tumor growth effectively with low toxicity and side effects. Taken together, the as-prepared delivery vehicles are a simple and safe nano-platform that improves the antitumor efficacy of VEGF siRNA and ITZ, which allows the repositioning of the generic drug ITZ as a great candidate for antitumor therapy.

Chemo-Phototherapy with Carfilzomib-Encapsulated TiN Nanoshells Suppressing Tumor Growth and Lymphatic Metastasis.

The design of nanomedicine for cancer therapy, especially the treatment of tumor metastasis has received great attention. Proteasome inhibition is accepted as a new strategy for cancer therapy. Despite being a big breakthrough in multiple myeloma therapy, carfilzomib (CFZ), a second-in-class proteasome inhibitor is still unsatisfactory for solid tumor and metastasis therapy. In this study, hollow titanium nitride (TiN) nanoshells are synthesized as a drug carrier of CFZ. The TiN nanoshells have a high loading capacity of CFZ, and their intrinsic inhibitory effect on autophagy synergistically enhances the activity of CFZ. Due to an excellent photothermal conversion efficiency in the second near-infrared (NIR-II) region, TiN nanoshell-based photothermal therapy further induces a synergistic anticancer effect. In vivo study demonstrates that TiN nanoshells readily drain into the lymph nodes, which are responsible for tumor lymphatic metastasis. The CFZ-loaded TiN nanoshell-based chemo-photothermal therapy combined with surgery offers a remarkable therapeutic outcome in greatly inhibiting further metastatic spread of cancer cells. These findings suggest that TiN nanoshells act as an efficient carrier of CFZ for realizing enhanced outcomes for proteasome inhibitor-based cancer therapy, and this work also presents a "combined chemo-phototherapy assisted surgery" strategy, promising for future cancer treatment.

Abstract 1047: Combinatorial anticancer therapy strategy using a pan-class I glucose transporter inhibitor with chemotherapy and target drugs in vitro and in vivo

Abstract Non-Small Cell Lung Cancer (NSCLC) is the most common type of lung cancer, accounting for 84% of all lung cancer diagnoses. While there are current standard treatments for NSCLC, these treatments may cause severe side effects, drug resistance, or lead to ineffective treatment, recurrence of the cancer, and death. It has been shown that most cancer types are “addicted” to glucose, and are sensitive and vulnerable to glucose deprivation, making the inhibition of glucose transport into these cells an attractive anticancer strategy. DRB18 is a small molecule proprietary compound that has been shown to target and inhibit class I glucose transporters (GLUTs, GLUT1-4), which are responsible for the uptake of glucose into cells, particularly these types of cancer cells. DRB18 has been shown to be effective in inhibiting cancer cell growth in vitro and in vivo without noticeable side effects.1 While this may be a promising anticancer therapy by itself, combining DRB18 with another anticancer drug that has a totally different anticancer mechanism should substantially increase the efficacy of the treatment while potentially minimizing the rate of resistance and recurrence of the cancer without increasing unwanted side effects. This research focuses on combining DRB18 with FDA-approved target drugs Trametinib and Brigatinib, the FDA-approved chemotherapy drug Paclitaxel, and a glutamine transporter inhibitor (V-9302). Thus, the treatment groups are vehicle, each of the previously mentioned drugs alone, as well as DRB18+Trametinib, DRB18+Brigatinib, DRB18+Paclitaxel, and DRB18+V-9302. This study tests the hypothesis that, due to their different anticancer mechanisms, the combination of DRB18 with these anticancer drugs will have a synergistic anticancer effect. Preliminary in vitro data and an in vivo pilot tumor study in nude mice, using human NSCLC A549 cells, have shown the improved anticancer efficacy of the combinatorial approach by further reducing tumor growth when compared with single drug treatment. The results of a larger nude mouse study, as well as basic mechanistic studies in vitro, that are currently underway will be presented later at the AACR meeting. This combination therapy has great therapeutic implications and the potential to benefit cancer patients for decades to come. 1. Shriwas P, Roberts D, Li Y, Wang L, Qian Y, Bergmeier S, Hines J, Adhicary S, Nielsen C, &amp; Chen X. (2021). A small molecule pan-class I glucose transporter inhibitor reduces cancer cell proliferation in vitro and tumor growth in vivo by targeting glucose-based metabolism. Cancer and Metabolism, 9 (14). Citation Format: Lindsey M. Bachmann, Pratik Shriwas, Ryan A. Ward, Liyi Wang, Stephen C. Bergmeier, Yunsheng Li, Xiaozhuo Chen. Combinatorial anticancer therapy strategy using a pan-class I glucose transporter inhibitor with chemotherapy and target drugs in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1047.