Inhibit Tumor Proliferation Research Articles

RRP9 promotes gemcitabine resistance in pancreatic cancer via activating AKT signaling pathway

BackgroundPancreatic cancer (PC) is a highly lethal malignancy regarding digestive system, which is the fourth leading factor of cancer-related mortalities in the globe. Prognosis is poor due to diagnosis at advanced disease stage, low rates of surgical resection, and resistance to traditional radiotherapy and chemotherapy. In order to develop novel therapeutic strategies, further elucidation of the molecular mechanisms underlying PC chemoresistance is required. Ribosomal RNA biogenesis has been implicated in tumorigenesis. Small nucleolar RNAs (snoRNAs) is responsible for post-transcriptional modifications of ribosomal RNAs during biogenesis, which have been identified as potential markers of various cancers. Here, we investigate the U3 snoRNA-associated protein RRP9/U3-55 K along with its role in the development of PC and gemcitabine resistance.MethodsqRT-PCR, western blot and immunohistochemical staining assays were employed to detect RRP9 expression in human PC tissue samples and cell lines. RRP9-overexpression and siRNA-RRP9 plasmids were constructed to test the effects of RRP9 overexpression and knockdown on cell viability investigated by MTT assay, colony formation, and apoptosis measured by FACS and western blot assays. Immunoprecipitation and immunofluorescence staining were utilized to demonstrate a relationship between RRP9 and IGF2BP1. A subcutaneous xenograft tumor model was elucidated in BALB/c nude mice to examine the RRP9 role in PC in vivo.ResultsSignificantly elevated RRP9 expression was observed in PC tissues than normal tissues, which was negatively correlated with patient prognosis. We found that RRP9 promoted gemcitabine resistance in PC in vivo and in vitro. Mechanistically, RRP9 activated AKT signaling pathway through interacting with DNA binding region of IGF2BP1 in PC cells, thereby promoting PC progression, and inducing gemcitabine resistance through a reduction in DNA damage and inhibition of apoptosis. Treatment with a combination of the AKT inhibitor MK-2206 and gemcitabine significantly inhibited tumor proliferation induced by overexpression of RRP9 in vitro and in vivo.ConclusionsOur data reveal that RRP9 has a critical function to induce gemcitabine chemoresistance in PC through the IGF2BP1/AKT signaling pathway activation, which might be a candidate to sensitize PC cells to gemcitabine.Graphical -NNMLsihmhHqHA_x8RjJniVideo abstract

Cascade Immune Activation of Self-Delivery Biomedicine for Photodynamic Immunotherapy Against Metastatic Tumor.

Photodynamic therapy (PDT) can generate reactive oxygen species (ROS) to cause cell apoptosis and induce immunogenic cell death (ICD) to activate immune response, becoming a promising antitumor modality. However, the overexpressions of indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand 1 (PD-L1) on tumor cells would reduce cytotoxic T cells infiltration and inhibit the immune activation. In this paper, a simple but effective nanosystem is developed to solve these issues for enhanced photodynamic immunotherapy. Specifically, it has been constructed a self-delivery biomedicine (CeNB) based on photosensitizer chlorine e6 (Ce6), IDO inhibitor (NLG919), and PD1/PDL1 blocker (BMS-1) without the need for extra excipients. Of note, CeNB possesses fairly high drug content (nearly 100%), favorable stability, and uniform morphology. More importantly, CeNB-mediated IDO inhibition and PD1/PDL1 blockade greatly improve the immunosuppressive tumor microenvironments to promote immune activation. The PDT of CeNB not only inhibits tumor proliferation but also induces ICD response to activate immunological cascade. Ultimately, self-delivery CeNB tremendously suppresses the tumor growth and metastasis while leads to a minimized side effect. Such simple and effective antitumor strategy overcomes the therapeutic resistance against PDT-initiated immunotherapy, suggesting a potential for metastatic tumor treatment in clinic.

A novel prognostic model for prostate cancer based on androgen biosynthetic and catabolic pathways.

Prostate cancer (PCa) is one of the most common malignancies in males globally, and its pathogenesis is significantly related to androgen. As one of the important treatments for prostate cancer, androgen deprivation therapy (ADT) inhibits tumor proliferation by controlling androgen levels, either surgically or pharmacologically. However, patients treated with ADT inevitably develop biochemical recurrence and advance to castration-resistant prostate cancer which has been reported to be associated with androgen biosynthetic and catabolic pathways. Thus, gene expression profiles and clinical information of PCa patients were collected from TCGA, MSKCC, and GEO databases for consensus clustering based on androgen biosynthetic and catabolic pathways. Subsequently, a novel prognostic model containing 13 genes (AFF3, B4GALNT4, CD38, CHRNA2, CST2, ADGRF5, KLK14, LRRC31, MT1F, MT1G, SFTPA2, SLC7A4, TDRD1) was constructed by univariate cox regression, lasso regression, and multivariate cox regression. Patients were divided into two groups based on their risk scores: high risk (HS) and low risk (LS), and survival analysis was used to determine the difference in biochemical recurrence-free time between the two. The results were validated on the MSKCC dataset and the GEO dataset. Functional enrichment analysis revealed some pivotal pathways that may have an impact on the prognosis of patients including the CDK-RB-E2F axis, G2M checkpoint, and KRAS signaling. In addition, somatic mutation, immune infiltration, and drug sensitivity analyses were performed to further explore the characteristics of HS and LS groups. Besides, two potential therapeutic targets, BIRC5 and RHOC, were identified by us in prostate cancer. These results indicate that the prognostic model may serve as a predictive tool to guide clinical treatment and provide new insight into the basic research in prostate cancer.

Multifunctional Hollow MnO2 @Porphyrin@Bromelain Nanoplatform for Enhanced Photodynamic Therapy.

Photodynamic therapy (PDT) has been showing great potential in cancer treatment. However, the efficacy of PDT is always limited by the intrinsic hypoxic tumor microenvironment (TME) and the low accumulation efficiency of photosensitizers in tumors. To address the issue, a multifunctional hollow multilayer nanoplatform (H-MnO2 @TPyP@Bro)comprising manganese dioxide, porphyrin (TPyP) and bromelain (Bro), is developed for enhanced photodynamic therapy. MnO2 catalyzes the intracellular hydrogen peroxide (H2 O2 ) to produce oxygen (O2 ), reversing the hypoxic TME in vivo. The generated O2 is converted into singlet oxygen (1 O2 ) by the TPyP shell under near-infrared light, which can inhibit tumor proliferation. Meanwhile, the Bro can digest collagen in the extracellular matrix around the tumor, and can promote the accumulation of H-MnO2 @TPyP@Bro in the deeper tumor tissue, further improving the therapeutic effect of PDT. In addition, MnO2 can react with the overexpressed glutathione in TME to release Mn2+ . Consequently, Mn2+ not only induces chemo-dynamic therapy based on Fenton reaction by converting H2 O2 into hydroxyl radicals, but also activates the Mn2+ -based magnetic resonance imaging. Therefore, the developed H-MnO2 @TPyP@Bro nanoplatform can effectively modulate the unfavorable TME and overcome the limitations of conventional PDT for cancer diagnostic and therapeutic.

Unlocking the potential of iridium and ruthenium arene complexes as anti-tumor and anti-metastasis chemotherapeutic agents

It is a major challenge to design novel multifunctional metal-based chemotherapeutic agents for anti-tumor and anti-metastasis applications. Two complexes (OA-Ir and OA-Ru) were synthesized via CuAAC (copper-catalyzed azide-alkyne cycloaddition) reaction from nontoxic Ir-N3 or Ru-N3 species and low toxic alkynyl precursor OA-Alkyne, and exhibited satisfactory anti-tumor and anti-metastasis pharmacological effects. Conjugation of Oleanolic acid (OA) and metal-arene species significantly enhanced the cytotoxicity in A2780 cells compared to the precursors through mitochondrial-induced autophagy pathway. Moreover, the two complexes could inhibit the cell metastasis and invasion through damage of actin dynamics and down-regulation of MMP2/MMP9 proteins. Combination of two precursors improved the lipophilicity and biocompatibility, simultaneously enhanced the cell uptake and the mitochondrial accumulation of metal-arene complexes, which caused mitochondrial membrane potential damage, oxidative phosphorylation, ATP depletion and autophagy. Besides, OA-Ir and OA-Ru displayed excellent activity to disintegrate the 3D multicellular tumor spheroids, showing potential for the treatment of solid tumors. This work provides a new way for developing novel metal-based complexes via CuAAC reaction for simultaneously inhibiting tumor proliferation and metastasis.

Porphyrin Centered Paclitaxel Tetrameric Prodrug Nanoassemblies as Tumor-Selective Theranostics for Synergized Breast Cancer Therapy.

Although having undergone decades of development, nanoparticulate drug delivery vehicles for efficient cancer therapy remain a challenge, confined by low drug loading, instability, and poor cancer tissue selectivity. A self-assembled prodrug, the combination of prodrug strategy and the self-assembly merits, represents a special chemical entity which spontaneously organizes into supramolecular composites with defined architecture, therefore also providing a strategy to develop new medications. Paclitaxel (PTX) is still among the most generally prescribed chemotherapeutics in oncology but is restricted by poor solubility. Although photodynamic therapy, with its noninvasive features and barely developed drug resistance, signifies an alternative tool to suppress life-threatening cancer, sole use hardly fulfills its potential. To this end, a reduction-activatable heterotetrameric prodrug with the photosensitizer is synthesized, then formulated into self-assembled nanoparticles (NPs) for tumor imaging and combined chemo- and photodynamic therapy. Coating the NPs with amphiphilic polymer distearylphosphatidylethanolamine-polyethylene glycol-arginine-glycine-aspartate (DSPE-PEG-RGD) offers high stability and enables cancer tissue targeting. The as-prepared NPs enlighten disease cells and reveal more potent cytotoxicity comparing to PTX and the photosensitizer alone. Furthermore, the NPs selectively accumulates into tumors and synergistically inhibits tumor proliferation with reduced side effects in mice.

Manganese-based Prussian blue nanoparticles inhibit tumor proliferation and migration via the MAPK pathway in pancreatic cancer.

Pancreatic cancer (PC) is one of the deadliest gastrointestinal malignancies. Advances in molecular biology and surgery have significantly improved survival rates for other tumors in recent decades, but clinical outcomes for PC remained relatively unchanged. Chemodynamic therapy (CDT) and Photothermal therapy (PTT) represent an efficient and relatively safe cancer treatment modality. Here, we synthesized Mn-doped Prussian blue nanoparticles (MnPB NPs) through a simple and mild method, which have a high loading capacity for drugs and excellent CDT/PTT effect. Cell line experiments in vitro and animal experiments in vivo proved the safety of MnPB NPs. We stimulated the PC cells with MnPB NPs and performed transwell migration assays. The migration of PC cells was reduced company with the decrease of two classical proteins: matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). Moreover, MnPB NPs induced ferroptosis, which mediated the MAPK pathway and achieved tumor elimination in nude mice. This effective and safe strategy controlled by irradiation represents a promising strategy for pancreatic cancer.

Most probable trajectory of a tumor model with immune response subjected to asymmetric Lévy noise

This paper is devoted to making realistic prediction for the trajectory transition of tumor cells induced by stochastic disturbances. To maintain better consistency with reality, an asymmetric Lévy noise is incorporated in a tumor–immune model. The corresponding Fokker–Planck equation is derived by the adjoint operator method. The transition behaviors of tumor cells are measured by maximizing the probability density function of system trajectories, namely, the most probable trajectory. The numerical algorithm for obtaining the most probable trajectory is offered. Based on the numerical calculations, the effect of Lévy noise on the evolution trajectories of tumor cells is discussed to explore the optimal parameters controlling or even eradicating tumor. It is found that by adjusting noise parameters, Lévy noise can induce the transition of tumor from the high concentration stable state toward the low concentration stable state or even to the tumor extinction state. When the skewness parameter is negative, Lévy noise with the stability index less than 1.0 and larger noise intensity is in favor of inhibiting tumor proliferation. While when the skewness parameter is positive, Lévy noise with the stability index larger than 1.0 and smaller noise intensity promotes the decrease of tumor cells.

A lipid droplet-specific near-infrared automatic oxygen-supplied AIEgen for photodynamic therapy and metastasis inhibition of hypoxic tumors

TTIMN NPs prepared based on TTIMN has the function of targeting lipid droplet to induce tumor regression by depleting GSH and inactivating GPX4. Meanwhile, the mode of TTIMN NPs catalyzed the conversion of O2−• was also clarified according to in vivo experiments, which indicated it could initiate a series of O2−•-mediated bio-catalytic reactions to gain autonomously generated O2 inside solid tumors. TTIMN NPs sensitized O2−• formation even under severe O2 shortage environment, and a part of it would be converted into highly toxic OH•, subsequently triggering the release of cytochrome c and activating the cascade of the Caspase family that ultimately led to cell apoptosis. Self-generated O2 inhibited tumor proliferation and metastasis mainly by interfering with HIF-related signaling and downregulating DNA methylation. TTIMN NPs has less systemic toxicity in blood systems and no effect on major organs, and blocked tumor progression by maintaining self-metabolism and immune system stability.

Antitumor Immunotherapy of Sialic Acid and/or GM1 Modified Coenzyme Q10 Submicron Emulsion.

Immunotherapy is a novel therapeutic approach for controlling and killing tumor cells by stimulating or reconstituting the immune system, among which T cells serve as immune targets. Herein, we used coenzyme Q10 (CoQ10), which has both immune activation and avoids adverse reactions, as a model drug and developed four CoQ10 submicron emulsions modified with sialic acid (SA) and/or monosialotetrahexosyl ganglioside (GM1). On the one hand, SA interacts with L-selectins on the surface of T cells after entering the circulatory system, leading to activation of T cells and enhancement of antitumor immune responses. On the other hand, owing to its immune camouflage, GM1 can prolong the circulation time of the preparation in the body, thereby increasing the accumulation of the drug at the tumor site. In vitro and in vivo experiments showed that SA-modified preparations exhibited stronger immune activation and inhibition of tumor proliferation. Pharmacokinetic experiments showed that GM1-modified preparations have longer circulation times in vivo. However, SA and GM1 co-modification did not produce a synergistic effect on the preparation. In conclusion, the SA-modified CoQ10 submicron emulsion (Q10-SE) showed optimal antitumor efficacy when administered at a medium dose (6mg CoQ10 kg-1). In this study, the submicron emulsion model was used as a carrier, and the tumor-bearing mice were used as animal models. In addition, CoQ10 submicron emulsion was modified with SA-CH with active targeting function and/or GM1 with long-circulation function to explore the antitumor effects of different doses of CoQ10 submicron emulsion, and to screen the best tumor immunotherapy formulations of CoQ10.

Bioinformatic analysis of FOXN3 expression and prognostic value in pancreatic cancer.

In most cancers, forkhead box N3 (FOXN3) acts as a transcriptional inhibitor to suppress tumor proliferation, but in pancreatic cancer, the opposite effect is observed. To confirm and investigate this phenomenon, FOXN3 expression in various carcinomas was determined using GEPIA2 and was found to be highly expressed in pancreatic cancer. Kaplan-Meier plotter was then used for survival analysis, revealing that high FOXN3 expression in pancreatic cancer might be associated with a poor prognosis. Similarly, clinical samples collected for immunohistochemical staining and survival analysis showed consistent results. The RNA-seq data of pancreatic cancer patients from the TCGA were then downloaded, and the differential expression gene set was obtained using R for gene set enrichment analysis (GSEA). The intersection of the above gene sets and FOXN3-related genes was defined as related differentially expressed gene sets (DEGs), and enrichment analysis was performed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Finally, we analyzed the relationship between FOXN3 and immune infiltration in pancreatic cancer. Collectively, our findings reveal that FOXN3 is involved in the occurrence and progression of pancreatic cancer and may be useful as a prognostic tool in pancreatic cancer immunotherapy.

Enhanced Acoustic Droplet Vaporization through the Active Magnetic Accumulation of Drug-Loaded Magnetic Particle-Encapsulated Nanodroplets (MPE-NDs) in Cancer Therapy.

The application of drug-loaded nanodroplets is still limited by their insufficient accumulation owing to the enhanced permeability and retention (EPR) effect failure in cancer therapy. To overcome these limitations, we propose an alternative magnetic particle-encapsulated nanodroplet (MPE-ND) with outstanding biosafety and magnetic targeting by encapsulating fluorinated Fe3O4-SiO2 nanoparticles inside the liquid core of the nanodroplets. Meanwhile, doxorubicin (DOX) can be stably loaded into the shell through both electrostatic and hydrophobic interactions to obtain drug-loaded MPE-NDs. Both in vitro and in vivo experiments have consistently demonstrated that drug-loaded MPE-NDs can significantly increase the local drug concentration and enhance the damage of tumor tissues through acoustic droplet vaporization under a static magnetic field (eADV therapy). Histological examination reveals that eADV therapy efficiently suppresses tumor proliferation by inducing apoptosis, destroying supply vessels, and inhibiting neovascularization. Drug-loaded MPE-NDs can be expected to open a new gateway for ultrasound-triggered drug delivery and cancer treatment.

Molecular insights and therapeutic implications of nanoengineered dietary polyphenols for targeting lung cancer: part II.

Flavonoids represent a major group of polyphenolic compounds. Their capacity to inhibit tumor proliferation, cell cycle, angiogenesis, migration and invasion is substantially responsible for their chemotherapeutic activity against lung cancer. However, their clinical application is limited due to poor aqueous solubility, low permeability and quick blood clearance, which leads to their low bioavailability. Nanoengineered systems such as liposomes, nanoparticles, micelles, dendrimers and nanotubes can considerably enhance the targeted action of the flavonoids with improved efficacy and pharmacokinetic properties, and flavonoids can be successfully translated from bench to bedside through various nanoengineering approaches. This review addresses the therapeutic potential of various flavonoids and highlights the cutting-edge progress in the nanoengineered systems that incorporate flavonoids for treating lung cancer.

A LETM2-Regulated PI3K-Akt Signaling Axis Reveals a Prognostic and Therapeutic Target in Pancreatic Cancer.

Simple SummaryLEMT2 was a newly discovered protein-encoding gene with little cancer research and an unclear mechanism. This study aimed to illustrate LETM2 as the crucial oncogene for tumor progression in pancreatic ductal adenocarcinoma (PDAC). We analyzed the expression level and prognostic value of LETM2 in multiple cancers using pan-cancer analysis and found that the LETM2 expression was the most significantly related to the dismal prognosis of PDAC. Immunohistochemical analyses showed that high LETM2 expression was correlated with poor outcomes of PDAC. In in vitro and in vivo experiments, LETM2 knockdown significantly inhibited tumor proliferation and metastasis, while LETM2 overexpression exerted the opposite effects. Then, we suggested that LETM2 may facilitate tumor progression by activating downstream PI3K-Akt signaling pathway in PDAC. In conclusion, the study enhanced our understanding of the LETM2-regulated PI3K-Akt signaling axis served as a prognostic and therapeutic target of pancreatic cancer.Pancreatic ductal adenocarcinoma (PDAC) is one of the highest mortalities malignant tumors, which is characterized by difficult diagnosis, rapid progression and high recurrence rate. Nevertheless, PDAC responds poorly to conventional therapies, which highlights the urgency to identify novel prognostic and therapeutic targets. LEMT2 was a newly discovered protein-encoding gene with little cancer research and an unclear mechanism. Thus, this study aimed to illustrate LETM2 as the crucial oncogene for tumor progression in PDAC. In this study, we analyzed the expression level and prognostic value of LETM2 in multiple cancers using pan-cancer analysis. The analyses based on the TCGA-GTEx dataset indicated that the LETM2 expression was obviously elevated in several cancers, and it was the most significantly related to the dismal prognosis of PDAC. Subsequently, we demonstrated the functional role and mechanism of LETM2 by clinical sample evaluation, and in in vitro and in vivo experiments. Immunohistochemical analyses showed that high expression of LETM2 was correlated with poor outcomes of PDAC. Moreover, we demonstrated that LETM2 knockdown significantly inhibited tumor proliferation and metastasis, and promoted cell apoptosis, while LETM2 overexpression exerted the opposite effects. Finally, the impairment caused by LETM2-knockdown could be recovered via excitation of the PI3k-Akt pathway in vitro and in vivo animal models, which suggested that LETM2 could activate the downstream PI3K-Akt pathway to participate in PDAC progression. In conclusion, the study enhanced our understanding of LETM2 as an oncogene hallmark of PDAC. LETM2 may facilitate tumor progression by activating the PI3K-Akt signaling pathway, which provides potential targets for the diagnosis, treatment, and prognosis of pancreatic cancer.

The Effects of Oncolytic Pseudorabies Virus Vaccine Strain Inhibited the Growth of Colorectal Cancer HCT-8 Cells In Vitro and In Vivo.

Simple SummaryOncolytic viruses have emerged as a viable therapy for cancers, and we explored the oncolytic effects of pseudorabies virus on colorectal cancer cells. The replication capacity and cytotoxic effect of the virus were investigated on colorectal cancer cells, meanwhile, the antitumor ability and safety were evaluated in a mouse tumor transplantation model tumor transplantation. For the first time, we found that the attenuated live vaccine strain of pseudorabies virus used in this study showed better anti-tumor activity. These results set the stage for subsequent clinical trials of tumor therapy using oncolytic viruses in non-primates and humans.Oncolytic viral therapy is a promising treatment approach for a variety of tumor forms. Although a number of studies have demonstrated that the pseudorabies virus (PRV) may be applied as an oncolytic carrier, the anti-colorectal cancer impact of the virus and the mechanism of its cytotoxic effect remain elusive. In this study, the replication capacity and cell activity of PRV attenuated live vaccines Bartha K61 and HB98 in HCT-8 cells in vitro were investigated. Next, the antitumor ability and safety were evaluated in a mouse model of HCT-8 tumor transplantation. Both PRV strains were able to suppress tumor growth and HB98 showed higher safety and efficiency than the Bartha K61 strain. Finally, flow cytometry and immunohistochemistry examination were performed to investigate its possible cytotoxic mechanism. The results showed that PRV inhibited tumor proliferation both in vitro and in vivo by inducing apoptosis. In summary, our study discovered for the first time that the live attenuated PRV has an oncolytic effect on HCT-8 cells with high efficacy and safety.

Enhanced anti-glioma efficacy of doxorubicin with BRD4 PROTAC degrader using targeted nanoparticles.

Current treatment of glioma is hampered due to the physical blood-brain barrier (BBB) and the resistance to traditional chemotherapeutic agents. Herein, we proposed a combined treatment strategy based on Cyclo (Arg-Gly-Asp-d-Phe-Lys) (cRGDfk) peptides-modified nanoparticle named cRGD-P in a self-assembly method for the co-delivery of doxorubicin (DOX) and BRD4 PROTAC degrader ARV-825 (ARV). Molecular dynamics simulations showed that cRGD-P could change its conformation to provide interaction sites for perfectly co-loading DOX and ARV. The cRGD-P/ARV-DOX exhibited an average size of 39.95 ​nm and a zeta potential of −0.25 ​mV. Increased expression of BRD4 in glioma cells was observed after being stimulated by cRGD-P/DOX, confirming one of the possible mechanisms of DOX resistance and the synergistic tumor inhibition effect of BRD4 degrading ARV combined with DOX. In the study, the combination of DOX and ARV in the cRGD-P nanoparticle system exhibited synergistic suppression of tumor growth in glioma cells on account of cell cycle arrest in the G2/M phase and the activation of tumor cells apoptosis-related pathways including triggering caspase cascade and downregulating Bcl-2 as well as upregulating Bax. The cRGD-P/ARV-DOX system could effectively suppress the heterotopic and orthotopic growth of glioma by increasing tumor apoptosis, inhibiting tumor proliferation, and decreasing tumor angiogenesis in vivo. Therefore, the cRGD-modified nanoparticle to co-deliver DOX and ARV provides a potential platform for exploiting a more effective and safer combination therapy for glioma.

Applications and mechanisms of the cyclin-dependent kinase 4/6 inhibitor, PD-0332991, in solid tumors.

Abnormal CDK4/6-Rb-E2F signal transduction is a common finding in tumors and is a driving factor for the excessive proliferation of various tumor cells. PD-0332991, a highly specific, small molecule inhibitor for CDK4 and 6, has been shown to inhibit tumor growth by abrogating the phosphorylating capacity of CDK4/6 and suppressing Rb phosphorylation. It has been promoted for the treatment of breast cancer and potentially for other tumor types such as liver cancers, lung cancers and sarcomas. Due to the risk of monotherapy resistance, PD-0332991 is commonly used in combination with other drugs. Such combination treatments have proved able to inhibit tumor proliferation more effectively, induce stronger senescence and apoptosis, and enhance the efficiency of immunotherapy. Therefore, tumor cells with senescence induced by PD-0332991 are now used as ideal screening tools of cytolytic drugs with more efficient and thorough anti-tumor properties. With more extensive understandings about the branching points between senescence and apoptosis, it is possible to refine the dosage of PD-0332991. Better characterization of resistant cells, of inhibitors and of adverse effects such as leukopenia are needed to overcome obstacles in the use of PD-0332991. In this review of PD-0332991 research, we hope to provide guidance of transitions from laboratory findings to clinical applications of PD-0332991 and to facilitate PD-0332991-based multi-inhibitor combination therapies for various tumors.

Hierarchical Assembly of Flexible Biopolymer Polyphosphate-Manganese into Nanosheets.

Polyphosphate (polyP) is one of the most compact inorganic polyanionic biopolymers that participates in various physiological processes. However, the development of polyP-based nanomaterials is still in its infancy. Here, biocompatible polyphosphate-manganese nanosheets are designed and synthesized by a hierarchical assembly strategy. The thickness and the lateral size of the resulting polyP-Mn nanosheets (PMNSs) are 5nm and 120-130nm, respectively. Molecular dynamics simulations suggested that the polyP-hexadecyl trimethyl ammonium bromide flat structure possesses a strong aggregating capacity and serves as the template for the 2D assembly of polyP-Mn. The PMNSs can activate the inflammatory response of macrophages resulting in the recovery of innate immunological functions to inhibit tumor proliferation. This work has initiated a new direction in constructing layered polyP-based nanomaterials and provides guidance for biocompatible and biodegradable biopolymer-based materials in the regulation of innate responses.

Co-administration of MDR1 and BCRP or EGFR/PI3K inhibitors overcomes lenvatinib resistance in hepatocellular carcinoma.

Lenvatinib is the first-line treatment for hepatocellular carcinoma (HCC), the most common type of primary liver cancer; however, some patients become refractory to lenvatinib. The underlying mechanism of lenvatinib resistance (LR) in patients with advanced HCC remains unclear. We focused on exploring the potential mechanism of LR and novel treatments of lenvatinib-resistant HCC. In particular, we established a Huh7 LR cell line and performed in vitro, bioinformatic, and biochemical assays. Additionally, we used a Huh7-LR cell-derived xenograft mouse model to confirm the results in vivo. Following LR induction, multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP) transporters were markedly upregulated, and the epidermal growth factor receptor (EGFR), MEK/ERK, and PI3K/AKT pathways were activated. In vitro, the co-administration of elacridar, a dual MDR1 and BCRP inhibitor, with lenvatinib inhibited proliferation and induced apoptosis of LR cells. These effects might be due to inhibiting cancer stem-like cells (CSCs) properties, by decreasing colony formation and downregulating CD133, EpCAM, SOX-9, and c-Myc expression. Moreover, the co-administration of gefitinib, an EGFR inhibitor, with lenvatinib retarded proliferation and induced apoptosis of LR cells. These similar effects might be caused by the inhibition of EGFR-mediated MEK/ERK and PI3K/AKT pathway activation. In vivo, co-administration of lenvatinib with elacridar or gefitinib suppressed tumour growth and angiogenesis. Therefore, inhibiting MDR1 and BCRP transporters or targeting the EGFR/PI3K pathway might overcome LR in HCC. Notably, lenvatinib should be used to treat HCC after LR induction owing to its role in inhibiting tumour proliferation and angiogenesis. Our findings could help develop novel and effective treatment strategies for HCC.

Structure, selenization modification, and antitumor activity of a glucomannan from Platycodon grandiflorum

Platycodon grandiflorum is consumed popularly as a nutritional and healthy plant in East Asia, which has multiple medicinal functions. As an exploration to elucidate the beneficial ingredients, an acetylated glucomannan (PGP40-1) was purified from P. grandiflorum. Structural analysis showed that PGP40-1 was composed of →4)-β-Manp-(1→, →4)-β-Glcp-(1→, →6)-β-Glcp-(1→, and terminal α-Glcp-(1→. PGP40-1 was found to possess weak antitumor activity in vitro, which was thus modified to afford a selenized polysaccharide (Se-PGP40-1) by the HNO3/Na2SeO3 method. Se-PGP40-1 showed significant antitumor activity in cell and zebrafish models, which could inhibit tumor proliferation and migration by inducing cell apoptosis and blocking angiogenesis. The research not only clarifies the ingredients of P. grandiflorum with high economical value, but also affords a potential antitumor agent originating from the plant polysaccharide.