Chemotherapeutic Drug Docetaxel Research Articles

Cell Membrane-Camouflaged Chitosan-Polypyrrole Nanogels Co-Deliver Drug and Gene for Targeted Chemotherapy and Bone Metastasis Inhibition of Prostate Cancer.

The development of functional nanoplatforms to improve the chemotherapy outcome and inhibit distal cancer cell metastasis remains an extreme challenge in cancer management. In this work, a human-derived PC-3 cancer cell membrane-camouflaged chitosan-polypyrrole nanogel (CH-PPy NG) platform, which can be loaded with chemotherapeutic drug docetaxel (DTX) and RANK siRNA for targeted chemotherapy and gene silencing-mediated metastasis inhibition of late-stage prostate cancer in a mouse model, is reported. The prepared NGs with a size of 155.8nm show good biocompatibility, pH-responsive drug release profile, and homologous targeting specificity to cancer cells, allowing for efficient and precise drug/gene co-delivery. Through in-vivo antitumor treatment in a xenografted PC-3 mouse tumor model, it is shown that such a CH-PPy NG-facilitated co-delivery system allows for effective chemotherapy to slow down the tumor growth rate, and effectively inhibits the metastasis of prostate cancer to the bone via downregulation of the RANK/RANKL signaling pathway. The created CH-Ppy NGs may be utilized as a promising platform for enhanced chemotherapy and anti-metastasis treatment of prostate cancer.

Overcoming biological barriers BBB/BBTB by designing PUFA functionalised lipid-based nanocarriers for glioblastoma targeted therapy

A major obstacle for chemotherapeutics in Glioblastoma (GB) is to reach the tumour cells due to the presence of the blood-brain barrier (BBB) and chemoresistance of anticancer drugs. The present study reports two polyunsaturated fatty acids, gamma-linolenic acid (GLA) and alpha-linolenic acid (ALA) appended nanostructured lipid carriers (NLCs) of a CNS negative chemotherapeutic drug docetaxel (DTX) for targeted delivery to GB. The ligand appended DTX-NLCs demonstrated particle size < 160 nm, PDI < 0.29 and a negative surface charge. The successful linkage of GLA (41 %) and ALA (30 %) ligand conjugation to DTX- NLCs was confirmed by diminished surface amino groups on the NLCs, lower surface charge and FTIR profiling. Fluorophore labelled GLA-DTX-NLCs and ALA-DTX-NLCs permeated the in-vitro 3D BBB model with Papp values of 1.8 × 10−3 and 1.9 × 10−3 cm/s respectively. Following permeation, both formulations showed enhanced uptake by GB immortalised cells while ALA-DTX-NLCs showed higher uptake in patient-derived GB cells as evidenced in an in-vitro 3D blood brain tumour barrier (BBTB) model. Both surface functionalised formulations showed higher internalisation in GB cells as compared to bare DTX-NLCs. ALA-DTX-NLCs and GLA-DTX-NLCs showed 13.9-fold and 6.8-fold higher DTX activity respectively at 24 h as indicated by IC50 values when tested in patient-derived GB cells. ALA-DTX-NLCs displayed better efficacy than GLA-DTX-NLCs when tested against 3D tumour spheroids and patient-derived cells. These novel formulations will contribute widely to overcoming biological barriers for treating glioblastoma.

CD44-targeted nanoparticles for co-delivery of docetaxel and an Akt inhibitor against colorectal cancer

New strategies to develop drug-loaded nanocarriers with improved therapeutic efficacy are needed for cancer treatment. Herein we report a novel drug-delivery nanosystem comprising encapsulation of the chemotherapeutic drug docetaxel (DTX) and recombinant fusion of a small peptide inhibitor of Akt kinase within an elastin-like recombinamer (ELR) vehicle. This combined approach is also precisely targeted to colorectal cancer cells by means of a chemically conjugated DNA aptamer specific for the CD44 tumor marker. This 53 nm dual-approach nanosystem was found to selectively affect cell viability (2.5 % survival) and proliferation of colorectal cancer cells in vitro compared to endothelial cells (50 % survival), and to trigger both apoptosis- and necrosis-mediated cell death. Our findings also show that the nanohybrid particles remain stable under physiological conditions, trigger sustained drug release and possess an adequate pharmacokinetic profile after systemic intravenous administration. In vivo assays showed that these dual-approach nanohybrids significantly reduced the number of tumor polyps along the colorectal tract in a murine colorectal cancer model. Furthermore, systemic administration of advanced nanohybrids induced tissue recovery by improving the morphology of gastrointestinal crypts and the tissue architecture. Taken together, these findings indicate that our strategy of an advanced dual-approach nanosystem allows us to achieve successful controlled release of chemotherapeutics in cancer cells and may have a promising potential for colorectal cancer treatment.

The first experience of using prostate cancer organoids as a model for personalized selection of drugs

Background. A promising experimental approach to the personalized selection of treatment regimens is the study of the sensitivity of tumor cells to drugs in vitro on tumor organoids.Aim. To generate a culture of prostate tumor organoids and to assess the effectiveness of the chemotherapeutic drug docetaxel used to treat prostate cancer on this culture.Materials and methods. The initial tissue was dissociated using gentleMACS Octo homogenizer. Next, the cells were cultured in matrix Matrigel with addition of a serum-free complete nutrient medium. For histological analysis, organoids were fixed in a 10 % formalin solution, followed by staining with hematoxylin and eosin according to the standard protocol. Cell viability was assessed using MTS assay.Results. In this work, we generated a new culture of prostate cancer cells. The histological analysis confirmed that the resulting organoids consist of tumor epithelial cells. As a result of the cytotoxic test, it was shown that in this case docetaxel (82.9 %; p = 0.32) didn’t reduce statistically significantly the viability of prostate cancer cells compared to the control.Conclusion. The use of tumor organoids of prostate cancer for selection of an optimal treatment regimen is a promising experimental technology, however, further research is necessary for its introduction into practice.

Molecular docking studies of Brucein D as a potential inhibitor of the Bcl-2 anti-apoptotic protein

Link of Video Abstract: https://youtu.be/JOzTSty10v4Background: Brucein D (BrD), a quassinoid isolated from Brucea javanica fruit, reportedly demonstrates anti-tumor activity. Bcl-2 is an anti-apoptotic protein that inhibits apoptosis and leads to cancer progression. This study aims to evaluate the inhibitory effect of BrD against the anti-apoptotic protein Bcl-2 by molecular docking study. Methods: We investigated the activity of BrD against Bcl-2 through molecular docking in silico compared to the chemotherapeutic drugs doxorubicin and docetaxel. Molecular docking analysis was conducted using the Lipinski rule of five drug-likeness analyses, PASS Online prediction, PyRx v0.8, Discovery Studio DS BIOVIA 2016 v16, and PyMol v2.4. Results: Current results show that BrD is qualified as a drug and can pass cell membranes without toxicity. The PASS prediction also shows that BrD can be activated as an anti-neoplastic inside the human body with Pa higher than Pi. BrD can make a constant and stable bond to Bcl-2 with a binding energy of -8.3 kcal/mol, almost equal to doxorubicin and docetaxel. BrD can form six types of hydrogen bonds that show stability to temperature and pressure. Conclusion: BrD has shown to be a promising alternative for an anti-cancer drug by inhibiting the Bcl-2 anti-apoptotic protein with low toxicity in normal cells.

Modulation of Reoviral Cytolysis (I): Combination Therapeutics.

Patients with stage IV gastric cancer suffer from dismal outcomes, a challenge especially in many Asian populations and for which new therapeutic options are needed. To explore this issue, we used oncolytic reovirus in combination with currently used chemotherapeutic drugs (irinotecan, paclitaxel, and docetaxel) for the treatment of gastric and other gastrointestinal cancer cells in vitro and in a mouse model. Cell viability in vitro was quantified by WST-1 assays in human cancer cell lines treated with reovirus and/or chemotherapeutic agents. The expression of reovirus protein and caspase activity was determined by flow cytometry. For in vivo studies, athymic mice received intratumoral injections of reovirus in combination with irinotecan or paclitaxel, after which tumor size was monitored. In contrast to expectations, we found that reoviral oncolysis was only poorly correlated with Ras pathway activation. Even so, the combination of reovirus with chemotherapeutic agents showed synergistic cytopathic effects in vitro, plus enhanced reovirus replication and apoptosis. In vivo experiments showed that reovirus alone can reduce tumor size and that the combination of reovirus with chemotherapeutic agents enhances this effect. Thus, we find that oncolytic reovirus therapy is effective against gastric cancer. Moreover, the combination of reovirus and chemotherapeutic agents synergistically enhanced cytotoxicity in human gastric cancer cell lines in vitro and in vivo. Our data support the use of reovirus in combination with chemotherapy in further clinical trials, and highlight the need for better biomarkers for reoviral oncolytic responsiveness.

The Oncogenic Protein Kinase/ATPase RIOK1 Is Up-Regulated via the c-myc/E2F Transcription Factor Axis in Prostate Cancer

The atypical protein kinase/ATPase RIO kinase (RIOK)-1 is involved in pre-40S ribosomal subunit production, cell-cycle progression, and protein arginine N-methyltransferase 5 methylosome substrate recruitment. RIOK1 overexpression is a characteristic of several malignancies and is correlated with cancer stage, therapy resistance, poor patient survival, and other prognostic factors. However, its role in prostate cancer (PCa) is unknown. In this study, the expression, regulation, and therapeutic potential of RIOK1 in PCa were examined. RIOK1 mRNA and protein expression were elevated in PCa tissue samples and correlated with proliferative and protein homeostasis-related pathways. RIOK1 was identified as a downstream target gene of the c-myc/E2F transcription factors. Proliferation of PCa cells was significantly reduced with RIOK1 knockdown and overexpression of the dominant-negative RIOK1-D324A mutant. Biochemical inhibition of RIOK1 with toyocamycin led to strong antiproliferative effects in androgen receptor-negative and -positive PCa cell lines with EC50 values of 3.5 to 8.8 nmol/L. Rapid decreases in RIOK1 protein expression and total rRNA content, and a shift in the 28S/18S rRNA ratio, were found with toyocamycin treatment. Apoptosis was induced with toyocamycin treatment at a level similar to that with the chemotherapeutic drug docetaxel used in clinical practice. In summary, the current study indicates that RIOK1 is a part of the MYC oncogene network, and as such, could be considered for future treatment of patients with PCa.

Self-assembled nanocomposites of carboxymethyl β-dextran/protamine sulfate for enhanced chemotherapeutic drug sensitivity of triple-negative breast cancer by autophagy inhibition via a ternary collaborative strategy

Drug resistance in cancer chemotherapy is a major confounding factor affecting the effectiveness of chemotherapeutic agents, thereby leading to poor clinical outcomes. Most chemotherapeutic drugs can induce protective autophagy and increase the resistance of tumors to chemotherapeutic drugs and reduce effective drug delivery to tumor cells. In this study, a tri-drug nanocomposite (NP) delivery system was devised using carboxymethyl β-dextran (CMD) and protamine sulfate (PS), two natural materials with good bio-compatibility. They were designed to carry the chemotherapeutic drug docetaxel (DTX), the autophagy inhibitor chloroquine (CQ), and Atg5 siRNA to cancer cells. The CQ + DTX + Atg5 siRNA NPs was driven by electrostatic interaction and self-assembly methods. The breast cancer cell line MDA-MB-231 was used for both cell culture and establishing mouse xenograft model. Our findings demonstrated that CQ and Atg5 siRNA encapsulated in NPs could enhance the sensitivity of tumor cells to DTX. The NPs exhibited remarkable considerable therapeutic effects for treating triple-negative breast cancer (TNBC) and good biosafety. Therefore, we established a novel multifunctional nanoplatform based on CMD and PS that enhances chemotherapeutic drug sensitivity through an autophagy inhibition strategy, providing new opportunities to overcome conventional drug resistance and enhance therapeutic efficiency against TNBC.

Inhibition of thioredoxin reductase 1 by vulpinic acid suppresses the proliferation and migration of human breast carcinoma

AimsIt was aimed to investigate the thioredoxin reductase 1 (TrxR1)-targeted anticancer effect of vulpinic (VA) and lecanoric (LA) acids, which are lichen secondary metabolites, on breast cancer MCF-7 and MDA-MB-453 cell lines, and to compare the effectiveness of this potential effect against commercial chemotherapeutic drugs carboplatin and docetaxel. Main methodsThe anticancer effects of both lichen metabolites were evaluated by XTT, flow cytometry analysis, cell scratch, and transwell migration assays. Apoptotic results were also confirmed by qPCR and western blot. Changes in TrxR1 were investigated in gene and protein expressions and enzyme activity levels. Key findingsVA suppressed the proliferation of MCF-7 and MDA-MB-453 cells in a dose- and time-dependent manner, and the IC50 values were calculated as 22.92 μg/ml and 95.65 μg/ml, respectively. As for LA, it did not have a considerable antiproliferative effect on both cell lines. VA had stronger cytotoxicity than both chemotherapeutic drug in MCF-7 cells and showed antiproliferative activity closer to carboplatin in MDA-MB-453 cells. qPCR, western blot, and flow cytometry analysis results revealed that VA did not induce apoptosis in both cell lines. In contrast, VA caused cell cycle arrest, significantly. Migration assay results showed that VA suppressed migration in both cells. VA induced the gene expression of TrxR1 while inhibiting its protein expression and enzymatic activity in both cell lines. SignificanceThe findings reveal that vulpinic acid may be a novel inhibitor candidate on TrxR1 and could be considered a potential chemotherapeutic agent for breast cancer treatment, especially in MCF-7 cells.

Enhanced anti-breast cancer efficacy of co-delivery liposomes of docetaxel and curcumin.

The successful treatment of breast cancer is hampered by toxicity to normal cells, impaired drug accumulation at the tumor site, and multidrug resistance. We designed a novel multifunctional liposome, CUR-DTX-L, to co-deliver curcumin (CUR) and the chemotherapeutic drug docetaxel (DTX) for the treatment of breast cancer in order to address multidrug resistance (MDR) and the low efficacy of chemotherapy. The mean particle size, polydispersity index, zeta potential, and encapsulation efficiency of CUR-DTX-L were 208.53 ± 6.82nm, 0.055 ± 0.001, -23.1 ± 2.1mV, and 98.32 ± 2.37%, respectively. An in vitro release study and CCK-8 assays showed that CUR-DTX-L has better sustained release effects and antitumor efficacy than free drugs, the antitumor efficacy was verified by MCF-7 tumor-bearing mice, the CUR-DTX-L showed better antitumor efficacy than other groups, and the in vivo pharmacokinetic study indicated that the plasma concentration-time curve, mean residence time, and biological half-life time of CUR-DTX-L were significantly increased compared with free drugs, suggesting that it is a promising drug delivery system for the synergistic treatment of breast cancer.

Redox-responsive hyaluronic acid-based nanoparticles for targeted photodynamic therapy/chemotherapy against breast cancer

Specific cellular uptake and sufficient drug release in tumor tissues are important for effective cancer therapy. Hyaluronic acid (HA), a skeleton material, could specifically bind to cluster determinant 44 (CD44) receptors highly expressed on the surface of tumor cells to realize active targeting. Cystamine (cys) is sensitive highly reductive environment inside tumor cells and was used as a connecting arm to connect docosahexaenoic acid (DHA) and chlorin e6 (Ce6) to the HA skeleton to obtain redox-sensitive polymer HA-cys-DHA/Ce6 (CHD). Nanoparticles were fabricated and loaded with chemotherapeutic drug docetaxel (DTX) by physical encapsulation. The prepared nanoparticles had significantly increased uptake by MCF-7 cells that overexpressed CD44 receptors, and DTX was effectively released at high reducing condition. Compared with mono-photodynamic therapy (PDT) or mono-chemotherapy, the prepared nanoparticles exhibited superior anti-tumor effect by inhibiting microtubule depolymerization, blocking cell cycle and generating reactive oxygen species (ROS). In vivo anti-tumor experiments proved that DTX/CHD nanoparticles had the best antitumor response versus DTX and CHD nanoparticles under near-infrared (NIR) irradiation. These studies revealed that redox-responsive DTX-loaded CHD nanoparticles held great potential for the treatment of breast cancer.

Thiophene donor for NIR-II fluorescence imaging-guided photothermal/photodynamic/chemo combination therapy

Organic fluorophores/photosensitizers have been widely used in biological imaging and photodynamic and photothermal combination therapy in the first near-infrared (NIR-I) window. However, their applications in the second near-infrared (NIR-II) window are still limited primarily due to low fluorescence quantum yields (QYs). Here, a boron dipyrromethene (BDP) is created as a molecularly engineered thiophene donor unit with high QYs to the redshift. Thiophene insertion initiates substantial redshifts of the absorbance as compared to its counterparts in which iodine is introduced. The fluorescent molecule can be triggered by an NIR laser with a single wavelength, thereby producing emission in the NIR-II windows. Single NIR laser-triggered phototherapeutic nanoparticles (NPs) are developed by encapsulating the BDP and the chemotherapeutic drug docetaxel (DTX) by using a synthetic amphiphilic poly(styrene-co-chloromethyl styrene)-graft-poly(ethylene glycol) functionalized with folic acid (FA). These BDP-T-N-DTX-FA NPs not only show superior solubility and high singlet oxygen QY (ΦΔ=62%) but also demonstrate single NIR laser-triggered multifunctional characteristics. After intravenous administration of the NPs into 4T1 tumor-bearing mice, the accumulation of the NPs in the tumor showed a high signal-to-background ratio (11.8). Furthermore, 4T1 tumors in mice were almost eradicated by DTX released from the BDP-T-N-DTX-FA NPs under single NIR laser excitation and the combination of photodynamic therapy (PDT) and photothermic therapy (PTT). Statement of significanceThe application of organic photosensitizers is still limited primarily due to low fluorescence quantum yields (QYs) in the second near-infrared (NIR-II) window. Here, a boron dipyrromethene (BDP) as a molecularly engineered thiophene donor unit with high QYs to the redshift is created. Phototherapeutic nanoparticles (NPs) are developed by encapsulating the BDP and docetaxel (DTX) using a synthetic amphiphilic poly(styrene-co-chloromethyl styrene)-graft-poly(ethylene glycol) functionalized with folic acid (FA). These BDP-T-N-DTX-FA NPs not only show high singlet oxygen QY (ΦΔ=62%) but also demonstrate single NIR laser-triggered multifunctional characteristics and a high signal-to-background ratio (11.8). Furthermore, 4T1 tumors in mice were almost eradicated by DTX released from the BDP-T-N-DTX-FA NPs under single NIR laser excitation and the PDT/PTT combination therapy.

Oral administration co-delivery nanoparticles of docetaxel and bevacizumab for improving intestinal absorption and enhancing anticancer activity

In this study, to improve the intestinal absorption of small molecule chemotherapeutic drug docetaxel (DTX) and macromolecular monoclonal antibody drug bevacizumab (BVZ), we designed and prepared a type of co-delivery nanoparticles for the oral administration of DTX and BVZ. Carboxymethyl chitosan (CMC) and poly(lactic-co-glycolic acid) (PLGA) were used as the carrier of DTX nanoparticles (CPNPDTX), and methoxy polyethylene glycol-poly (β-amino ester) (mPEG-PAE) was used as the carrier of BVZ nanoparticles (PPNPBVZ). Then, the two nanoparticles were physically mixed in mass ratios to form mixed co-delivery nanoparticles, which was named as CPNPDTX&PPNPBVZ. The nanoparticles were characterized with pH-sensitive drug release property. CPNPDTX&PPNPBVZ could significantly increase the bioavailability of DTX and BVZ according to the more cellular uptake in Caco-2 cells and the higher absorption in the intestinal tissue. Compared with free DTX and BVZ, CPNPDTX&PPNPBVZ showed excellent cytotoxic effects on A549 cells. Our study revealed the potential of co-delivery nanoparticles of binary mixture of chemotherapeutic small molecule and macromolecular antibody drug as an oral administration therapeutic system.

Current Status of Castration-Resistant Prostate Cancer Drug Therapy

ABSTRACT Objective: To explore the current therapies on castration-resistant prostate cancer (CRPC), such as drug therapy and radiotherapy. Recent Advances: Currently, CRPC is an incurable disease. CRPC treatment options available can only relieve symptoms and prolong the survival time. Because of the in-depth study of resistance mechanisms, various new drugs have been reported, including androgen synthetic inhibitor, abiraterone. Novel targeted therapy and immunotherapy have been thoroughly investigated. The recent advances in wellstudied radiotherapy and chemotherapy against CRCP have also been reviewed. In this review, we have summarized new generation hormone drugs (e.g., abiraterone, enzalutamid), chemotherapeutic drugs (docetaxel), targeted therapy drugs, immunotherapy drugs (Sipulecel-T), and radioactive drugs (Radium 223). The overall treatment goals include to prolong OS, to improve quality of life, to relieve symptoms, and to prevent complications in CRCP patients. Conclusions: The use of drug therapy in combination with other drugs might improve the efficacy of CRPC treatment and might help overcome drug resistance.

Tailoring functional nanostructured lipid carriers for glioblastoma treatment with enhanced permeability through in-vitro 3D BBB/BBTB models

The blood-brain barrier (BBB) and blood-brain tumour barrier (BBTB) pose a significant challenge to drug delivery to brain tumours, including aggressive glioblastoma (GB). The present study rationally designed functional nanostructured lipid carriers (NLC) to tailor their BBB penetrating properties with high encapsulation of CNS negative chemotherapeutic drug docetaxel (DTX). We investigated the effect of four liquid lipids, propylene glycol monolaurate (Lauroglycol® 90), Capryol® propylene glycol monocaprylate, caprylocaproylmacrogol-8-glycerides (Labrasol®) and polyoxyl-15-hydroxystearate (Kolliphor® HS15) individually and in combination to develop NLCs with effective permeation across in-vitro 3D BBB model without alteration in the integrity of the barrier. With desirable spherical shape as revealed by TEM and an average particle size of 123.3 ± 0.642 nm and zeta potential of −32 mV, DTX-NLCs demonstrated excellent stability for six months in its freeze-dried form. The confocal microscopy along with flow cytometry data revealed higher internalisation of DTX-NLCs in U87MG over SVG P12 cells. Micropinocytosis was observed to be one of the dominant pathways for internalisation in U87MG cells while clathrin-mediated pathway was more predominat in patient-derived glioblastoma cells. The NLCs readily penetrated the actively proliferating peripheral cells on the surface of the 3D tumour spheroids as compared to the necrotic core. The DTX-NLCs induced cell arrest through G2/M phase with a significant decrease in the mitochondrial reserve capacity of cells. The NLCs circumvented BBTB with high permeability followed by accumulation in glioblastoma cells with patient-derived cells displaying ~2.4-fold higher uptake in comparison to U87MG when studied in a 3D in-vitro model of BBTB/GB. We envisage this simple and industrially feasible technology as a potential candidate to be developed as GB nanomedicine.

LHRH-conjugated, PEGylated, poly-lactide-co-glycolide nanocapsules for targeted delivery of combinational chemotherapeutic drugs Docetaxel and Quercetin for prostate cancer

One of the major challenges in effective cancer chemotherapy is the severe systemic cytotoxicities of anticancer drugs on healthy tissues. The present study reports chemically modified polymeric nanocapsules (NCs) encapsulating combination of chemotherapeutic drugs Docetaxel (DTX) and Quercetin (QU) for its active targeting to prostate cancer (PCa). The active targeting was achieved by conjugating Luteinizing-hormone-releasing hormone (LHRH) ligand to poly-lactide-co-glycolide (PLGA) using polyethylene glycol (PEG) as a spacer. The structure of the conjugates was characterized and confirmed using 1H NMR and ATR-FTIR. The drug encapsulated NCs showed a homogenous size distribution with their size ranging between 120 and 150nm, and exhibited a negative zeta potential in the range of -20 to -40mV. The in vitro release studies highlighted the sustained drug release pattern from the respective NCs; while the PEG coating to polymeric NCs provided serum stability to the NCs. The in vitro biological evaluation of the NCs was conducted using PC-3 and LNCaP cell lines. The results of the cellular uptake studies showed a significantly higher untake of the LHRH targeted NCs, while the LHRH-targeted-PEGylated DTX: QU NCs exhibited higher caspase-3 activity. The cell viability assay results showed the enhanced cell inhibition activity of the combinatorial DTX: QU when compared to individual DTX. Further, higher cell cytotoxicity was achieved by LHRH-targeted DTX: QU NCs as compared to their free-form or non-targeted NCs. Finally, the results of in vivo tumor localization and in vivo antitumor activity studies complimented and upheld the in vitro results, demonstrating the beneficial role of PLGA-PEG-LHRH NCs encapsulating combination of DTX and QU in combating prostate cancer (PCa).

Potentiation of cancerous progression by LISCH7 via direct stimulation of TGFB1 transcription in triple-negative breast cancer.

As an aggressive breast cancer (BCa) subtype, triple-negative breast cancer (TNBC) responses poorly to chemotherapy and endocrine therapy, and usually has a worse prognosis. This is largely due to the lack of specific therapeutic targets, laying claim to an imperious demand to clarify the key signaling pathways potentiating TNBC progression. Herein, we report that expression levels of the liver-specific bHLH-Zip transcription factor (LISCH7), a recently identified key player in cancerous progression, preferentially enriched in TNBC in comparison with other BCa subtypes, and this upregulation was observed to be correlated to a poor survival outcome in patients with TNBC. Ablation of LISCH7 in TNBC cells impaired cell proliferation, reduced cell invasiveness, and enhanced sensitivity to the first-line chemotherapeutic drug docetaxel at both in vitro and in vivo levels. Importantly, concurrent induction of TGFB1, the gene encoding transforming growth factor-β1 (TGF-β1), an essential multipluripotent regulator of TNBC, was accompanied with these alterations in cancerous properties. We further showed that LISCH7 could directly bind to the TGFB1 promoter and stimulate TGFB1 transcription in TNBC cells. The recruitment of LISCH7 onto the TGFB1 chromatin and transactivation of TGFB1 were substantially augmented by treatment with the exogenous TGF-β1 in a time- and dose-dependent manner. Collectively, these findings suggest that LISCH7 and TGF-β1 form a reciprocal positive regulatory loop and cooperatively regulate cancerous progression in TNBC cells. Thus, simultaneous inhibition of both LISCH7 and TGF-β1 signaling may represent a more effective approach to counteract advanced TNBC.

Improving radio-chemotherapy efficacy of prostate cancer by co-deliverying docetaxel and dbait with biodegradable nanoparticles

Combining DNA damage repair inhibitors and chemotherapeutic agents is an emerging strategy in cancer treatment. In this study, we engineered the polycation nanoparticle (NP), which co-encapsulated DNA damage repair inhibitor Dbait and chemotherapeutic drug Docetaxel (Dtxl), using H1 nanopolymer (folate–-polyethylenimine600–cyclodextrin), and the size of H1/Dbait/Dtxl was about 117 nm. We demonstrated that H1/Dbait/Dtxl enhanced the efficiency of radio-chemotherapy in prostate cancer cells by CCK-8 assay and colony-forming assay. Importantly, the improvement of radio-chemotherapy of H1/Dbait/Dtxl in prostate cancer was also validated in vivo, and the NP did not have a high toxicity profile. The results of immunohistochemistry and western blot supported that the improved therapeutic efficacy was through inhibiting DNA damage repair signalling pathway. Our study supports further investigations using NP to co-deliver DNA damage repair inhibitors and chemotherapeutics to improve the therapeutic efficacy of cancer.

Glucosinolate-Degradation Products as Co-Adjuvant Therapy on Prostate Cancer in Vitro.

Glucosinolate-degradation products (GS-degradation products) are believed to be responsible for the anticancer effects of cruciferous vegetables. Furthermore, they could improve the efficacy and reduce side-effects of chemotherapy. The aim of the present study was to determine the cytotoxic effects of GS-degradation products on androgen-insensitive human prostate cancer (AIPC) PC-3 and DU 145 cells and investigate their ability to sensitize such cells to chemotherapeutic drug Docetaxel (DOCE). Cells were cultured under growing concentrations of allyl-isothiocyanate (AITC), sulforaphane (SFN), 4-pentenyl-isothiocyanate (4PI), iberin (IB), indole-3-carbinol (I3C), or phenethyl-isothiocyanate (PEITC) in absence or presence of DOCE. The anti-tumor effects of these compounds were analyzed using the trypan blue exclusion, apoptosis, invasion and RT-qPCR assays and confocal microscopy. We observed that AITC, SFN, IB, and/or PEITC induced a dose- and time-dependent cytotoxic effect on PC-3 and DU 145 cells, which was mediated, at least, by apoptosis and cell cycle arrest. Likewise, we showed that these GS-degradation products sensitized both cell lines to DOCE by synergic mechanisms. Taken together, our results indicate that GS-degradation products can be promising compounds as co-adjuvant therapy in prostate cancer.

GSH/pH dual-responsive supramolecular hybrid vesicles for synergistic enzymatic/chemo-tumor therapy

Supramolecular amphiphilic vesicles are promising carriers in tumor therapy due to their excellent loading capabilities for both hydrophilic and hydrophobic cargos, especially for biomacromolecules such as proteins, enzymes and plasmids. However, the poor circulating stability and unsatisfied therapeutic efficiency greatly limit their in vivo applications. To address these issues, herein, we design and develop a new kind of GSH/pH dual-responsive supramolecular hybrid vesicles (SHVs) to encapsulate and deliver simultaneously biomacromolecule glucose oxidase (GOD) and chemotherapeutic drug docetaxel (DTX) for synergistic enzymatic/chemo-tumor therapy. The SHVs are constructed by the self-assembly of β-CD-poly(ε-caprolactone), ferrocene-poly (acrylic acid) and pillar [5] arenes via the terminal β-CD/Fc host-guest interaction, followed by cross-linking with 3-mercaptopropyltrimethoxysilane and poly (ethylene glycol) modification. As a vehicle for both hydrophilic and hydrophobic cargos, the resulting GOD/DTX co-loaded SHVs exhibit excellent synergistic enzymatic/chemo-tumor therapeutic ability with a combination index (CI = 0.285) of GOD and DTX in cellular level and high tumor inhibitory rate of 95.3% in vivo. Consequently, the resulting hybrid vesicles can be used as efficient and safe carriers for biomacromolecules in further cancer therapy.