Antitumor Research Articles

Effect of the presence of berberine/curcumin on the binding of limonin to human serum albumin and antitumor activity in vitro

The competition among drugs for binding to plasma proteins is regarded as a pharmacokinetic drug interaction. Competition between antitumor agents and other drugs for plasma protein binding can alter the free concentration of the drug, potentially impacting its efficacy and increasing the risk of toxic side effects. Through a range of spectroscopic techniques, this study examined the interaction between limonin and human serum albumin (HSA) in the context of berberine (Ber) and curcumin (Cur) under physiological conditions to clarify the binding mechanisms of binary and ternary systems at the molecular level. As demonstrated by fluorescence quenching experiments, Static quenching was identified as the mechanism of interaction between HSA and limonin. The results of site competition experiments indicated that the binding site between limonin and HSA was site I, a result further supported by molecular docking simulations. Through the use of thermodynamic data calculations, it was determined that limonin forms a stable complex with HSA by establishing hydrogen bonds and van der Waals forces. Circular dichroism (CD) spectroscopy, three-dimensional (3D) fluorescence spectroscopy, and synchronous fluorescence spectroscopy (SFS) employed to validate the notion that limonin perturbed the microenvironment of amino acids and induced conformational changes in HSA. What’s more, the presence of Ber or Cur was found to have further modified the alterations observed in the interaction between the original HSA-limonin binary system. In vitro cellular experiments showed that interaction with HSA reduced the antitumor activity of limonin. In contrast, adding Ber or Cur increased the inhibition rate of tumor cells. The coexistence of both Ber and Cur significantly diminished limonin’s binding affinity to HSA. The current investigation enhances comprehension regarding the binding characteristics and interaction mechanisms involving limonin, Ber, Cur, and HSA. It explores the potential of HSA as a versatile drug carrier and furnishes theoretical underpinnings for co-administrative strategies.

Risks and benefits of anti-TNF therapy for ulcerative colitis in a patient with autoimmune hepatitis-related cirrhosis: Case report.

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by continuous inflammation of the colonic mucosa. Autoimmune hepatitis (AIH) is a chronic liver disease characterized by hypergammaglobulinemia, circulating autoantibodies, interface hepatitis, and favorable response to immunosuppression. An association between IBD and AIH is uncommon, and experts have suggested that in patients with overlapping IBD and AIH, the anti-tumor necrosis factor agents can be used. Therefore, this study reports a rare case of a patient with liver cirrhosis due to AIH and UC refractory to conventional treatment and discusses the risks and benefits of using anti-tumor necrosis factor in both conditions. A 28-year-old female presented with symptoms of diarrhea, abdominal pain, asthenia, and inappetence, accompanied by abdominal collateral circulation, anemia, alteration of liver enzymes, and elevation of C-reactive protein levels. The patient underwent a liver biopsy, which was consistent with liver cirrhosis due to AIH. Colonoscopy showed an inflammatory process throughout the colon, compatible with moderately active UC. The patient received mesalazine, azathioprine, and corticotherapy, with no control of the inflammatory process. Faced with refractoriness to drug treatment and side effects of corticosteroids with an increased risk of severe infection due to cirrhosis, we opted to use infliximab for the treatment of UC. The patient presented with a clinical response and infliximab therapy was maintained. Eight months after starting infliximab therapy, the patient developed pneumonia with complications from disseminated intravascular coagulation and died. AIH is a rare cause of elevated transaminase levels in patients with UC. The best treatment to control the 2 conditions should be evaluated with vigilance for the side effects of medications, mainly infections, especially in patients with cirrhosis.

Biohybrid hydrogel inhibiting β-klotho/HDAC3 axis for hepatocellular carcinoma treatment

Hepatocellular carcinoma (HCC), ranking as the fourth most prevalent cancer globally, has garnered significant attention due to its high invasiveness and mortality rates. However, drug therapies face challenges of inadequate efficacy and unclear mechanisms. Here, we propose a novel biohybrid hydrogel that targets β-klotho (KLB) for HCC treatment. As a dual-network hydrogel, this gel combines gelatin methacryloyl (GelMA) and polyvinyl alcohol (PVA) to ensure biocompatibility while enhancing controlled drug release. Notably, it exhibits good storage stability, high drug load capacity, and efficient water absorption. By introducing the HDAC3 inhibitor RGFP966, we can selectively inhibit the activation of KLB. This deactivation effectively blocks the FGF21-KLB signaling pathway and inhibits the progression of HCC. Importantly, we have successfully validated this unique phenomenon both in vivo and in vitro, providing substantial evidence for the efficacy of this hydrogel-based anti-tumor drug delivery system as a promising strategy for HCC treatment. This innovative research outcome brings new hope to the field of tumor therapy, providing a reliable theoretical foundation for future clinical applications.

A hydroxychloroquine platinum(IV) conjugate displaying potent antimetastatic activities by suppressing autophagy to improve the tumor microenvironment.

Protective autophagy is a promising target for antitumor drug exploration. A hydroxychloroquine (HCQ) platinum(IV) complex with autophagy suppressing potency was developed, which displayed potent antitumor activities with a TGI rate of 44.2% against 4T1 tumors in vivo and exhibited a rather lower toxicity than cisplatin. Notably, it exhibited satisfactory antimetastatic activities toward lung pulmonary metastasis models with an inhibition rate of 49.6% and was obviously more potent than CDDP, which has an inhibition rate of 21.6%. Mechanism detection revealed that it caused serious DNA damage and upregulated the expression of γ-H2AX and p53. More importantly, the incorporation of an autophagy inhibitor HCQ endowed the platinum(IV) complex with potent autophagy impairing properties by perturbing the lysosomal function in tumor cells, which promoted apoptosis synergistically with DNA injury. Then, the impaired autophagy further led to the suppression of hypoxia and inflammation in the tumor microenvironment by downregulating ERK1/2, HIF-1α, iNOS, caspase1 and COX-2. Adaptive immune response was improved by inhibiting the immune checkpoint PD-L1 and further increasing CD4+ and CD8+ T cells in tumors. Then, tumor metastasis was effectively inhibited by restraining angiogenesis through inhibiting VEGFA, MMP-9, and CD34.

Development of new LSM-83177 analogues as anti-tumor agents against colorectal cancer targeting p53-MDM2 interaction

LSM-83177, a phenoxy acetic acid derivative, is a small molecule reported for its promising anti-tumor properties. Via inhibiting the interaction between MDM2 and p53, LSM-83177 can elevate the active p53 levels within cells, thereby promoting apoptosis and inhibiting tumor growth. Also, LSM-83177 has been shown to inhibit GST activity in colorectal cancer HT29 cells. In the current work, novel LSM-83177 hydrazone analogs 5a-f, 7a-b, 10a-e, and 13a-b have been designed according to the structure features of LSM-83177 and their binding mode in the active site of MDM2. The anti-cancer activity of the newly synthesized analogs is evaluated against the HT29 cell line. The most potent compounds, 7a and 10a, showed IC50 = 12.48 and 10.44 µg/ml, respectively, when compared with Cisplatin (IC50 = 11.32 µg/ml) as a reference drug. Compounds 7a and 10a were introduced for further inspection for p53-MDM2 protein–protein interaction, where they displayed IC50 values of 3.65 and 11.08 µg/ml, respectively. Furthermore, hydrazones 7a and 10a increased the p-53 expression levels by 3.22– and 4.25-fold, respectively; in addition, they effectively reduced the GST expression levels in HT29 cancer cells with 0.56- and 0.30-fold increments in comparison to the untreated control.

Exploring intermolecular interaction between transporter protein, bovine serum albumin and antitumor drug Lorlatinib: Multispectral approaches combined with molecular simulation

In this paper, the intermolecular interaction of antitumor drug loratinib (LOR) with the transporter protein, bovine serum albumin (BSA) was researched utilizing multiple spectroscopic approaches combined with molecular modeling. The experimental outcomes showed that LOR entered the hydrophobic gap between the two subintervals of BSA (site II '), formed the ground-state complex with a stoichiometric ratio of 1:1, and statically quenched the endogenous fluorescence of BSA protein. During the intermolecular interaction between the two, the binding constant was with the interval of 104-106 M−1, indicating a moderate to strong affinity between the two. In addition, there was a non-radiative energy transfer from BSA to LOR, and binding with LOR diminished the α-helix content of BSA protein and affected slightly on the microenvironment surrounding the aromatic amino acids like Trp and Tyr residues. The binding of LOR to BSA was inhibited by most common metal ions, and only the Fe3+ ion promoted it. The outcomes of experiments as well as molecular dynamics simulation showed that the primary binding forces between LOR and BSA were hydrogen bonding, hydrophobic force and van der Waals force.

Application of Drug Repurposing Approach for Therapeutic Intervention of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD), represented by Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder of the gastrointestinal tract (GIT) characterized by chronic relapsing intestinal inflammation, abdominal pain, cramping, loss of appetite, fatigue, diarrhoea, and weight loss. Although the etiology of IBD remains unclear, it is believed to be an interaction between genes, and environmental factors, such as an imbalance of the intestinal microbiota, changing food habits, an ultra-hygiene environment, and an inappropriate immune system. The development of novel effective therapies is stymied by a lack of understanding of the aetiology of IBD. The current therapy involves the use of aminosalicylates, immunosuppressants, and corticosteroids that can effectively manage symptoms, induce and sustain remission, prevent complications, modify the course of the disease, provide diverse treatment options, showcase advancements in biologic therapies, and enhance the overall quality of life. However, the efficacy of current therapy is overshadowed by a plethora of adverse effects, such as loss of weight, mood swings, skin issues, loss of bone density, higher vulnerability to infections, and elevated blood pressure. Biologicals, like anti-tumour necrosis factor agents, can stimulate an autoimmune response in certain individuals that may diminish the effectiveness of the medication over time, necessitating a switch to alternative treatments. The response of IBD patients to current drug therapy is quite varied, which can lead to disease flares that underlines the urgent need to explore alternative treatment option to address the unmet need of developing new treatment strategies for IBD with high efficacy and fewer adverse effects. Drug repurposing is a novel strategy where existing drugs that have already been validated safe in patients for the management of certain diseases are redeployed to treat other, unindicated diseases. The present narrative review focuses on potential drug candidates that could be repurposed for the management of IBD using on-target and off-target strategies. It covers their preclinical, clinical assessment, mechanism of action, and safety profiles, and forecasts their appropriateness in the management of IBD. The review presents useful insights into the most promising candidates for repurposing, like anti-inflammatory and anti-apoptotic troxerutin, which has been found to improve the DSS-induced colitis in rats, an antiosteoarthritic drug diacetylrhein that has been found to have remarkable ameliorating effects on DSS-induced colitis via anti-oxidant and anti- inflammatory properties and by influencing both apoptosis and pyroptosis. Topiramate, an antiepileptic and anticonvulsant drug, has remarkably decreased overall pathophysiological and histopathological events in the experimental model of IBD in rodents by its cytokine inhibitory action.

Prostate cancer chemotherapy by intratumoral administration of Docetaxel-Mesoporous silica nanomedicines

Docetaxel (DTX) is a recommended treatment in patients with metastasic prostate cancer (PCa), despite its therapeutic efficacy is limited by strong systemic toxicity. However, in localized PCa, intratumoral (IT) administration of DTX could be an alternative to consider that may help to overcome the disadvantages of conventional intravenous (IV) therapy. In this context, we here present the first in vivo preclinical study of PCa therapy with nanomedicines of mesoporous silica nanoparticles (MSN) and DTX by IT injection over a xenograft mouse model bearing human prostate adenocarcinoma tumors. The efficacy and tolerability, the biodistribution and the histopathology after therapy have been investigated for the DTX nanomedicine and the free drug, and compared with the IV administration of DTX. The obtained results demonstrate that IT injection of DTX and DTX nanomedicines allows precise and selective therapy of non-metastatic PCa and minimize systemic diffusion of the drug, showing superior activity than IV route. This allows reducing the therapeutic dose by one order and widens substantially the therapeutic window for this drug. Furthermore, the use of DTX nanomedicines as IT injection promotes strong antitumor efficacy and drug accumulation at the tumor site, improving the results obtained with the free drug by the same route.

Biomimetic Nucleic Acid Drug Delivery Systems for Relieving Tumor Immunosuppressive Microenvironment.

Immunotherapy combats tumors by enhancing the body's immune surveillance and clearance of tumor cells. Various nucleic acid drugs can be used in immunotherapy, such as DNA expressing cytokines, mRNA tumor vaccines, small interfering RNAs (siRNA) knocking down immunosuppressive molecules, and oligonucleotides that can be used as immune adjuvants. Nucleic acid drugs, which are prone to nuclease degradation in the circulation and find it difficult to enter the target cells, typically necessitate developing appropriate vectors for effective in vivo delivery. Biomimetic drug delivery systems, derived from viruses, bacteria, and cells, can protect the cargos from degradation and clearance, and deliver them to the target cells to ensure safety. Moreover, they can activate the immune system through their endogenous activities and active components, thereby improving the efficacy of antitumor immunotherapeutic nucleic acid drugs. In this review, biomimetic nucleic acid delivery systems for relieving a tumor immunosuppressive microenvironment are introduced. Their immune activation mechanisms, including upregulating the proinflammatory cytokines, serving as tumor vaccines, inhibiting immune checkpoints, and modulating intratumoral immune cells, are elaborated. The advantages and disadvantages, as well as possible directions for their clinical translation, are summarized at last.

Intermediate-based virtual screening of c-Kit kinase inhibitors as potential anti-tumor agents via ab inito folding, molecular dynamics simulation, and molecular docking

Uncontrolled activation of c-Kit is closely related to the pathogenesis and progression of leukemia, gastrointestinal cancer, and other malignant diseases. Although there are several inhibitors available, due to the limitation of selectivity and the unfavorable side effects, designing and discovering highly selective inhibitors targeting c-Kit kinase, especially the gain of function mutation (for example c-Kit D816V), is still necessary. To identify novel c-Kit inhibitors, a metastable state-based virtual screening approach, which was successfully implemented in other kinase inhibitors, was employed in the current study. The results from our current study demonstrated the residues adjacent to the DFG motif within the activation loop could fold into short α-helices aside from the random coil, which was commonly found in the crystal structure. By expanding the conformation pool of the activation loop via PyRosetta-based ab initio folding protocol, we constructed a series of structural models of the c-Kit kinase intermediate between the inactive and active states. After evaluation of the thermal stability of the metastable state with molecular dynamics simulation, one structural model showed higher stability of α-helix, and the activation loop was retained. Considering the wild-type and D816V mutated KIT kinase shared similar metastable states during the kinase activation process, we developed a hypothesis that the identified intermediate might hold the potential to identify inhibitors targeting D816V mutations from the compound database. As expected, the intermediate structure showed higher selectivity to KIT D816V selective inhibitors, such as bezuclastinib, avapritinib, BLU-263, and elenestinib, than imatinib or masitinib. The virtual screening of the available KIT kinase inhibitor database further identified vorolanib, semaxanib, henatinib, and pexmetinib may possess potential inhibitory effects against wild type, as well as the mutated c-Kit kinase. The results from our current study not only proposed a novel structural model that could be used for the identification of selective c-Kit D816V inhibitors but also identified several potential inhibitors from available kinase inhibitors, which might shed new light on the design of new therapeutic approaches for c-Kit mutation-driven malignant diseases.

Evaluation of the in vivo acute toxicity and in vitro genotoxicity and mutagenicity of synthetic β-carboline alkaloids with selective cytotoxic activity against ovarian and breast cancer cell lines

The aim of this study was to evaluate the in vitro cytotoxic, genotoxic, and mutagenic potential and to determine the in silico ADME parameters of two synthetic β-carboline alkaloids developed as prototypes of antitumor agents (NQBio-06 and NQBio-21). Additionally, acute toxicity of the compounds was evaluated in mice. The results from the MTT assay showed that NQBio-06 presented higher cytotoxicity in the ovarian cancer cell line TOV-21G (IC50 = 2.5 µM, selectivity index = 23.7). NQBio-21 presented an IC50 of 6.9 µM and a selectivity index of 14.5 against MDA-MB-231 breast cancer cells. Comet assay results showed that NQBio-06 did not induce chromosomal breaks in vitro, but NQBio-21 was genotoxic with and without metabolic activation (S9 fraction). Micronucleus assay showed that both compounds were mutagenic. In addition, metabolic activation enhanced this effect in vitro. The in silico predictions showed that the compounds met the criteria set by Lipinski's rules, had strong prediction for intestinal absorption, and were possible substrates for P-glycoprotein. The in vivo results demonstrated that both the compounds exhibited low acute toxicity. These results suggest that the mechanisms underlying the cytotoxicity of NQBio-06 and NQBio-21 are related to DNA damage induction and that the use of S9 enhanced these effects. In vivo analysis showed signs of toxicity after a single administration of the compounds in mice. These findings highlight the potential of β-carboline compounds as sources for the development of new anticancer chemotherapeutic agents.

Evaluation of the antitumor activity of albendazole using Langmuir-Blodgett monolayers as surface mediated drug delivery system

This study demonstrates the application of Langmuir and Langmuir-Blodgett films as biomimetic drug reservoirs and delivery systems to investigate the effect of an anthelmintic on cancer cell culture. The repurposing of benzimidazole anthelmintics for cancer therapy due to their microtubule-inhibiting properties has gained attention, showing promising anticancer effects and tumor-suppressive properties. Although widely used in medicine, the low aqueous solubility of benzimidazole compounds poses challenges for studying their effects on cancer cells, requiring incorporation into various formulations. Our study demonstrates that incorporating albendazole into stable Palmitic Acid Langmuir monolayers, forming Langmuir-Blodgett films, significantly affects the proliferation of liver carcinoma cells. This report presents the initial findings of the effect of an antitumoral drug on cancer cell culture using a simple and repeatable methodology.

New insights into the function and mechanisms of piRNA PMLCPIR in promoting PM2.5-induced lung cancer

IntroductionExtensive studies have established the correlation between long-term PM2.5 exposure and lung cancer, yet the mechanisms underlying this association remain poorly understood. PIWI-interacting RNAs (piRNAs), a novel category of small non-coding RNAs, serve important roles in various diseases. However, their biological function and mechanism in PM2.5-induced lung cancer have not been thoroughly investigated. ObjectivesWe aimed to explore the oncogenic role of piRNA in lung cancer induced by PM2.5 exposure, as well as the underlying mechanisms. MethodsWe conducted a PM2.5-induced human lung epithelial cell malignant transformation model. Human samples were used to further verify the finding. In vitro proliferation, migration, and invasion assays were performed to study the function of piRNA. RNA-sequencing was used to elucidate the the mechanisms of how piRNA mediates cell functions. PiRNA pull-down and computational docking analysis were conducted to identify proteins that binding to piRNA. In vivo experiments were used to explore whether inhibition of PMLCPIR could have a therapeutic effect on lung cancer. ResultsWe identified a new up-regulated piRNA, termed PM2.5-induced lung cancer up-regulation piRNA (PMLCPIR), which promotes the proliferation of PM2.5-transformed cells and lung cancer cells. RNA sequencing revealed ITGB1 as a downstream target of PMLCPIR. Importantly, PMLCPIR binds to nucleolin (NCL) and increases the expression of its target gene, ITGB1, thereby activating PI3K/AKT signaling. The inhibition of PMLCPIR could promote apoptosis in lung cancer cells and enhance their chemosensitivity to anti-tumor drugs. ConclusionWe systematically identified the alterations of piRNA expression profiles in the PM2.5-induced malignant transformation model. Then, PMLCPIR was recognized as a novel oncogenic piRNA in PM2.5-induced lung cancer. Mechanically, PMLCPIR binds to NCL, enhancing ITGB1 expression and activating the ontogenetic PI3K/AKT signaling, potentially contributing to lung cancer progression. This study provides novel insights into the revelation of a new epigenetic regulator in PM2.5-induced lung cancer.

Design, synthesis, anti-tumor activity and mechanism of novel PROTACs as degraders of PD-L1 and inhibitors of PD-1/PD-L1 interaction

Currently, antibody drugs targeting programmed cell death ligand 1 (PD-L1) have achieved promising results in cancer treatment, while the development of small-molecule drugs lags behind. In this study, we designed and synthesized a series of PD-L1-degrading agents based on the PROTAC design principle, utilizing the PD-L1 inhibitor A56. Through systematic screening of ligands and linkers and investigating the structure–activity relationship of the degraders, we identified two highly active compounds, 9i and 9j. These compounds enhance levels of CD4+, CD8+, granzyme B, and perforin, demonstrating significant in vivo antitumor effects with a tumor growth inhibition (TGI) of up to 57.35 %. Both compounds facilitate the internalization of PD-L1 from the cell surface and promote its degradation through proteasomal and lysosomal pathways, while also maintaining inhibition of the PD-1/PD-L1 interaction. In summary, our findings provide a novel strategy and mechanism for developing biphenyl-based PROTAC antitumor drugs targeting and degrading PD-L1.

Design, synthesis and antitumor activity of 3,4,5-Trisubstituted Isoxazoles

In this study, 56 isoxazole derivatives were synthesized and their antitumor activity against 9 cancer cells, such as BXPC-3, MiaPaCa-2, PANC-1, MCF-7, HCT-116, HepG2, NCI-H460, A549 and B16 was detected. The results of pharmacological experiments indicated that most compounds exhibit good cytotoxicity against nine cancer cells. Among them, compound 14–3 has an IC50 of 2.4 μM for colon cancer cells HCT-116, which shows the best effect and is better than the broad-spectrum drug 5-Fluorouracil (5-Fu) for the treatment of colon cancer. In addition, 14–3 induces apoptosis and leads to cell cycle arrest in the G2/M phase. Cytotoxicity tests on human normal hepatocytes LO2 also demonstrates that 14–3 is less toxic than 5-Fu with no obvious toxicity. These results suggest that 14–3 is a potential candidate for the development of anti-tumor drugs.

Advances in the anti-tumor mechanisms of saikosaponin D.

Saikosaponin D, a saponin compound, is extracted from Bupleurum and is a principal active component of the plant. It boasts a variety of pharmacologic effects including anti-inflammatory, antioxidant, immunomodulatory, metabolic, and anti-tumor properties, drawing significant attention in anti-tumor research in recent years. Research indicates that saikosaponin D inhibits the proliferation of numerous tumor cells, curbing the progression of cancers such as liver, pancreatic, lung, glioma, ovarian, thyroid, stomach, and breast cancer. Its anti-tumor mechanisms largely involve inhibiting tumor cell proliferation, promoting tumor cell apoptosis, thwarting tumor-cell invasion, and modulating tumor cell autophagy. Moreover, saikosaponin D enhances the sensitivity to anti-tumor drugs and augments body immunity. Given its multi-faceted anti-tumor roles, saikosaponin D offers promising potential in anti-tumor therapy. This paper reviews recent studies on its anti-tumor effects, aiming to furnish new theoretical insights for clinical cancer treatments.

Revealing the impact of modified modules flexibility on gemcitabine prodrug nanoassemblies for effective cancer therapy

Prodrug nanoassemblies combine the advantages of prodrug strategies and nanotechnology have been widely utilized for delivering antitumor drugs. These prodrugs typically comprise active drug modules, response modules, and modification modules. Among them, the modification modules play a critical factor in improving the self-assembly ability of the parent drug. However, the impact of the specific structure of the modification modules on prodrug self-assembly remains elusive. In this study, two gemcitabine (GEM) prodrugs are developed using 2-octyl-1-dodecanol (OD) as flexible modification modules and cholesterol (CLS) as rigid modification modules. Interestingly, the differences in the chemical structure of modification modules significantly affect the assembly performance, drug release, cytotoxicity, tumor accumulation, and antitumor efficacy of prodrug nanoassemblies. It is noteworthy that the prodrug nanoassemblies constructed with flexible modifying chains (OD) exhibit improved stability, faster drug release, and enhanced antitumor effects. Our findings elucidate the significant impact of modification modules on the construction of prodrug nanoassemblies.

Epithelial-mesenchymal transition in chemoradiation-induced lung damage: Mechanisms and potential treatment approaches.

Pulmonary injury is one of the key restricting factors for the therapy of malignancies with chemotherapy or following radiotherapy for chest cancers. The lung is a sensitive organ to some severely toxic antitumor drugs, consisting of bleomycin and alkylating agents. Furthermore, treatment with radiotherapy may drive acute and late adverse impacts on the lung. The major consequences of radiotherapy and chemotherapy in the lung are pneumonitis and fibrosis. Pneumonitis may arise some months to a few years behind cancer therapy. However, fibrosis is a long-term effect that appears years after chemo/or radiotherapy. Several mechanisms such as oxidative stress and severe immune reactions are implicated in the progression of pulmonary fibrosis. Epithelial-mesenchymal transition (EMT) is offered as a pivotal mechanism for lung fibrosis behind chemotherapy and radiotherapy. It seems that pulmonary fibrosis is the main consequence of EMT after chemo/radiotherapy. Several biological processes, consisting of the liberation of pro-inflammatory and pro-fibrosis molecules, oxidative stress, upregulation of nuclear factor of κB and Akt, epigenetic changes, and some others, may participate in EMT and pulmonary fibrosis behind cancer therapy. In this review, we aim to discuss how chemotherapy or radiotherapy may promote EMT and lung fibrosis. Furthermore, we review potential targets and effective agents to suppress EMT and lung fibrosis after cancer therapy.

Nordic inflammatory bowel disease treatment strategy trial: protocol for the NORDTREAT randomised controlled biomarker-strategy trial

IntroductionThe absence of reliable prognostic markers poses a challenge to the management of inflammatory bowel disease (IBD). Patients with aggressive disease may not receive sufficient treatment with conventional ‘step-up’ therapy,...

Design, synthesis and biological evaluation of novel quinazoline-derived EGFR/HER-2 dual-target inhibitors bearing a heterocyclic-containing tail as potential anti-tumor agents

A series of novel quinazoline-derived EGFR/HER-2 dual-target inhibitors were designed and synthesized by heterocyclic-containing tail approach. The inhibitory activities against four human epidermal growth factor receptor (HER) isozymes (EGFR, HER-2, HER-3 and HER-4) of all new compounds so designed were investigated in vitro. Compound 12k was found to be the most effective and rather selective dual-target inhibitor of EGFR and HER-2 with inhibitory constant (IC50) values of 6.15 and 9.78 nM, respectively, which was more potent than the clinical used agent Lapatinib (IC50 = 8.41 and 9.41 nM). Meanwhile, almost all compounds showed excellent antiproliferative activities against four cancer cell models (A549, NCI-H1975, SK-BR-3 and MCF-7) and low damage to healthy cells. Among them, compound 12k also exhibited the most prominent antitumor activity. Moreover, the hit compound 12k could bind to EGFR and HER-2 stably in molecular docking and dynamics studies. The following wound healing assay revealed that compound 12k could inhibit the migration of SK-BR-3 cells. Further studies found that compound 12k could arrest cell cycle in the G0/G1 phase and induce SK-BR-3 cells apoptosis. Notably, compound 12k could effectively inhibit breast cancer growth with little toxicity in the SK-BR-3 cell xenograft model. Taken together, in vitro and in vivo results disclosed that compound 12k had high drug potential as a dual-target inhibitor of EGFR/HER-2 to inhibit breast cancer growth.