Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: Platinum-based chemotherapy is the recommended adjuvant treatment for patients with resectable, ALK-positive non-small-cell lung cancer (NSCLC). Data on the efficacy and safety of adjuvant alectinib as compared with chemotherapy in patients with resected ALK-positive NSCLC are lacking. METHODS: We conducted a global, phase 3, open-label, randomized trial in which patients with completely resected, ALK-positive NSCLC of stage IB (tumors ≥4 cm), II, or IIIA (as classified according to the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer and Union for International Cancer Control) were randomly assigned in a 1:1 ratio to receive oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy in four 21-day cycles. The primary end point was disease-free survival, tested hierarchically among patients with stage II or IIIA disease and then in the intention-to-treat population. Other end points included central nervous system (CNS) disease-free survival, overall survival, and safety. RESULTS: In total, 257 patients were randomly assigned to receive alectinib (130 patients) or chemotherapy (127 patients). The percentage of patients alive and disease-free at 2 years was 93.8% in the alectinib group and 63.0% in the chemotherapy group among patients with stage II or IIIA disease (hazard ratio for disease recurrence or death, 0.24; 95% confidence interval [CI], 0.13 to 0.45; P<0.001) and 93.6% and 63.7%, respectively, in the intention-to-treat population (hazard ratio, 0.24; 95% CI, 0.13 to 0.43; P<0.001). Alectinib was associated with a clinically meaningful benefit with respect to CNS disease-free survival as compared with chemotherapy (hazard ratio for CNS disease recurrence or death, 0.22; 95% CI, 0.08 to 0.58). Data for overall survival were immature. No unexpected safety findings were observed. CONCLUSIONS: Among patients with resected ALK-positive NSCLC of stage IB, II, or IIIA, adjuvant alectinib significantly improved disease-free survival as compared with platinum-based chemotherapy. (Funded by F. Hoffmann-La Roche; ALINA ClinicalTrials.gov number, NCT03456076.).

Exploring bi-carbazole-linked triazoles as inhibitors of prolyl endo peptidase via integrated in vitro and in silico study.

A serine protease called prolyl endopeptidase (PEP) hydrolyses the peptide bonds on the carboxy side of the proline ring. The excessive PEP expression in brain results in neurodegenerative illnesses like dementia, Alzheimer's disease, and Parkinson's disease. Results of the prior studies on antioxidant activity, and the non-cytotoxic effect of bi-carbazole-linked triazoles, encouraged us to extend our studies towards its anti-diabetic potential. Hence, for this purpose all compounds 1-9 were evaluated to reveal their anti-prolyl endo peptidase activity. Fortunately, seven compounds resulted into significant inhibitory capability ranging from 26 to 63 µM. Among them six compounds 4-9 exhibited more potent inhibitory activity with IC50 values 46.10 ± 1.16, 42.30 ± 1.18, 37.14 ± 1.21, 26.29 ± 0.76, 28.31 ± 0.64 and 31.11 ± 0.84 µM respectively, while compound 3 was the least active compound in the series with IC50 value 63.10 ± 1.58 µM comparing with standard PEP inhibitor bacitracin (IC50 = 125 ± 1.50 µM). Moreover, mechanistic study was performed for the most active compounds 7 and 8 with Ki values 24.10 ± 0.0076 and 23.67 ± 0.0084 µM respectively. Further, the in silico studies suggested that the compounds exhibited potential interactions and significant molecular conformations, thereby elucidating the structural basis for their inhibitory effects.

[Successful bridging therapy with alectinib prior to allogeneic stem cell transplantation for refractory ALK-positive anaplastic large cell lymphoma].

Although alectinib is effective for relapsed or refractory ALK-positive anaplastic large cell lymphoma (ALCL) and has a favorable safety profile, its role as a bridging therapy for allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the role of allo-HSCT itself in this setting are unknown. A 35-year-old man with ALK-positive ALCL experienced relapse after first-line therapy with CHOP. Brentuximab vedotin led to partial response and high-dose chemotherapy combined with autologous HSCT was performed. However, disease progressed 15 months after transplantation, and alectinib was initiated. Complete response (CR) was achieved after three months of treatment, and alectinib was continued for 5 months. After cessation of alectinib, allogeneic bone marrow transplantation from an HLA 1-locus mismatched unrelated donor was performed after conditioning with fludarabine, busulfan, and total body irradiation. GVHD prophylaxis consisted of tacrolimus and short-term methotrexate. The post-transplant course was unremarkable except for grade I acute GVHD. The lymphoma has not recurred for 2 years after allo-HSCT without resuming alectinib. The clinical course of our case suggests that alectinib bridging therapy and allo-HSCT are effective in relapsed/refractory ALK-positive ALCL.

Polymeric microenvironment enhancing polarity response sensitivity for discriminating lipid droplets in cancer cells.

Cellular micro-environment analysis via fluorescence probe has become a powerful method to explore the early-stage cancer diagnosis and pathophysiological process of relevant diseases. The polarity change of intracellular lipid droplets (LDs) is closely linked with disorders or diseases, which result in various physiological and pathological processes. However, the efficient design strategy for lipid droplet polarity probes with high sensitivity is lacking. To overcome this difficulty, two kinds of LDs-targeting and polarity-sensitive fluorescent probes containing carbazole and siloxane groups were rationally designed and synthesized. With the carbazole-based rotor and bridge-like siloxanes, two probes (P1 and P2) behave high sensitivity to polarity changes and show different fluorescent intensity in normal and cancer cells. Notably, polysiloxanes groups promoted the response sensitivity of the probes dramatically for the polymeric microenvironment. In addition, due to the polarity changes of LDs in cancer cells, the distinct fluorescent intensities in different channels of laser scanning confocal microscope were observed between NHA cell and U87 cells. This work could offer an opportunity to monitor the dynamic behaviors of LDs and further provide a powerful tool to be potentially applied in the early-stage diagnosis of cancer.

A new carbazole based fluorescent probe with AIE characteristic for detecting and imaging hydrazine in living cells, mungbean sprouts, Arabidopsis thaliana, and practical samples.

In this study, we report a new carbazole-malononitrile fluorescent probe CBC with an interesting aggregation-induced emission (AIE) characteristic. Probe CBC could rapidly and selectively detect hydrazine (N2H4) in ～100% aqueous media, and also exhibit an exceedingly low detection limit of 6.3 nM for sensitively detecting N2H4. The sensing mechanism of CBC towards N2H4 has been well demonstrated through the spectra of 1H NMR, HRMS and FTIR. Interestingly, probe CBC was applied to visualize and detect gaseous and aqueous N2H4 with sensitive color changes. Importantly, probe CBC was applied to effectively detect N2H4 in practical samples such as soil, human serum, human urine, plants, foods and beverages, as well as sensitively sense and image N2H4 in biological systems including living mungbean sprouts, Arabidopsis thaliana, and HeLa cells.

Treating anaplastic lymphoma kinase (ALK) fusion-driven metastatic non-small cell lung cancer (NSCLC) with alectinib through pregnancy.

Management of cancer during pregnancy requires careful consideration of risks and benefits from maternal and fetal perspectives. For advanced lung adenocarcinomas, with no targetable driver mutations, there is evidence-based guidance on the use of carboplatin-paclitaxel chemotherapy after first trimester. In contrast, for epidermal growth factor receptor (EGFR)-mutated or anaplastic lymphoma kinase (ALK)-rearranged metastatic lung adenocarcinomas, there is a paucity of clinical data on the safety of EGFR and ALK tyrosine kinase inhibitors to mother and fetus for official guidelines to recommend the use of these otherwise-first-line therapies in pregnancy. Considering this knowledge gap, we present a case of a young gravida 1 para 0 (G1P0) woman who continued alectinib 300 mg oral two times per day for ALK-rearranged metastatic lung adenocarcinoma throughout all 36 weeks of her pregnancy and delivered a healthy baby at term via caesarean section (C-section).

Carbazole and Quinazolinone Derivatives from a Fluoride-Tolerant Streptomyces Strain OUCMDZ-5511.

Six new 9H-carbazole derivatives (1-6) and nine previously reported compounds (7-15) were isolated from a fermented solid medium of the Thailand mangrove-derived Streptomyces strain, OUCMDZ-5511, under fluoride stress. Compounds 2-5, 12, and 15 were exclusively present in the fluoride-supplemented fermentation medium, while compounds 7-9, 13, and 14 were newly discovered natural products. The molecular structures of the compounds were identified by a spectroscopic analysis. The new compound 2 displayed antiquorum sensing activity against Chromobacterium violaceum ATCC 12472 by reducing the violacein production and inhibiting the biofilm formation in a concentration-dependent manner. The study revealed that compound 2 could be a novel potential inhibitor of quorum sensing.

Presence of carbazole and polyhalogenated carbazoles in human urine.

Exposure to carbazole (CZ) and polyhalogenated carbazoles (PHCZs) may pose a threat to human health, owing to their potential dioxin-like toxicity. Until now, the presence of these chemicals in the human urine from the general population is still unclear. Human urine samples (n = 210) were taken from the general population in Quzhou, China in this study, and were analyzed for CZ and 14 PHCZs. CZ and nine PHCZs were detected in collected human urine. CZ (detection frequency 100 %), 3-chlorocarbazole (3-CCZ; 88 %), 3,6-dichlorocarbzole (36-CCZ; 84 %), and 3-bromocarbazole (3-BCZ; 80 %) were more frequently detected. Among detected PHCZs, 3-CCZ (mean 0.49 ng/mL, < LOD-4.3 ng/mL) had comparatively higher urinary levels, followed by 3-BCZ (0.30 ng/L, < LOD-1.9 ng/mL) and 36-CCZ (0.20 ng/L, < LOD-1.4 ng/mL). Urinary concentrations of CZ in male participants (1.3 ± 0.26 ng/mL) were significantly (p < 0.05) higher than that in female participants (0.92 ± 0.24 ng/mL). No obvious trend in urinary concentrations with the age of participants was found for CZ and detected PHCZs. The mean daily excretion was found highest for CZ (31 ng/kg bw/day), followed by 3-CCZ (19 ng/kg bw/day) and 3-BCZ (8.5 ng/kg bw/day). This study provides the first data, to our knowledge, on the presence and levels of CZ and PHCZs in human urine, which is necessary for conducting the human exposure risk assessment.

Near-Infrared Light-Excited Quinolinium-Carbazole Small Molecule as Two-Photon Fluorescence Nucleic Acid Probe.

This article reports three new two-photon absorption (TPA) materials that are quinolinium-carbazole derivates. They are 3-(N-methyl-4-ethylquinolinium iodide)-9-ethylcarbazole (M4), 3-(N-methyl-4-ethylquinolinium iodide)-9-ethylcarbazole (H2), and 3-(N-methyl-4-ethylquinolinium iodide)-9-ethylcarbazole (H4). Their TPA cross-sections are 491, 515, and 512 GM, respectively. Under the excitation of near-infrared light, their fluorescence emission is about 650 nm. The compounds can stain nucleic acid DNA with the same level of nuclear localization as Hoechst 33342. Under continuous irradiation with a near-infrared laser, the three new compounds showed less fluorescence decay than DAPI, and the average fluorescence decay rates were 0.016%/s, 0.020%/s, and 0.023%/s. They are expected to become new two-photon fluorescent probes of nucleic acid DNA because of their excellent performance.

Identifying optimal ALK inhibitors in first- and second-line treatment of patients with advanced ALK-positive non-small-cell lung cancer: a systematic review and network meta-analysis.

OBJECTIVES: To compare the efficacy, safety and effects on quality of life of different ALK-inhibitors for global and Asian patients with advanced ALK-positive non-small-cell lung cancer (NSCLC). METHODS: The included RCTs were identified through a systematic search of PubMed, EMBASE, Cochrane Library, Clinical Trials.gov, and major cancer conferences. The assessment of progression-free survival (PFS), intracranial PFS, overall survival (OS), and patient-reported outcomes (PROs) was carried out using restricted mean survival time (RMST) model, fractional polynomial model and Royston-Parmar model. Time-invariant hazard ratio (HR) models were also used to validate and supplement the primary analysis. Objective response rate (ORR) and adverse events with any grade, grade 3-5 were assessed through a Bayesian network meta-analysis. The primary measures for OS, PFS, and PROs were HR and RMST. The odds ratio was the metric for evaluating safety, ORR, 12-month PFS rate, 24-month OS rate, and the 12-month non-deterioration rate of PROs. Subgroup analyses based on patient characteristics were performed. RESULTS: A total of fourteen studies (ten for first-line, four for second-line) consisting of nine treatments (chemotherapy, crizotinib, alectinib [600mg BID], low-dose alectinib [300mg BID], brigatinib, ceritinib, ensartinib, envonalkib, and lorlatinib) were included. In the first-line setting, alectinib showed a significant advantage over crizotinib and had the longest OS among all ALK-inhibitors. Compared to crizotinib, lorlatinib had the best efficacy regarding PFS for global patients, followed closely by alectinib and brigatinib. For Asian patients, alectinib significantly improved PFS compared to other treatments. In second-line, alectinib had the highest PFS for patients pretreated with crizotinib, followed by brigatinib, ceritinib and chemotherapy. Alectinib, irrespective of the dose, was the safest first-line option, whereas lorlatinib, brigatinib, and ceritinib showed poorer safety profiles. Alectinib was also the safest ALK-inhibitor for crizotinib-resistant patients. Brigatinib had the best performance in terms of PROs. CONCLUSIONS: Considering both efficacy and safety, alectinib appears to be the preferable treatment in first-line and second-line, particularly for Asian patients.

Chemical profile of the roots of Clausena lansium and their inhibitory effects of the over-activation in BV-2 microglial cells.

From the 95% ethanol aqueous extract of the roots of Clausena lansium, six previously undescribed alkaloids (1, 2a, 2b, 15, 24a, 24b), a pair of prenylated phenylpropenols (26a, 26b), two coumarins (27, 28), and two undescribed sesquiterpenes (37, 38) were isolated and identified using spectroscopic and electron circular dichroism data, together with thirty-two known compounds. The absolute configurations of three alkaloids (3a, 3b, 4a) were determined for the first time. In vitro assay showed that alkaloids 7, 10, 12, 19, and furanocoumarins 34, 35 displayed inhibitory effects on the production of nitric oxide in lipopolysaccharide (LPS)-induced BV-2 microglial cells, which were stronger than that of the minocycline (positive control). RT-PCR results indicated that indizoline (7) could inhibit the expression of pro-inflammatory factors (IL-1ß, TNF-α, and IL-6) in LPS-treated BV-2 cells.

The Protein Kinase A Inhibitor KT5720 Prevents Endothelial Dysfunctions Induced by High-Dose Irradiation.

High-dose irradiation can trigger numerous endothelial dysfunctions, including apoptosis, the overexpression of adhesion molecules, and alteration of adherens junctions. Altogether, these endothelial dysfunctions contribute to the development of tissue inflammation and organ damage. The development of endothelial dysfunctions may depend on protein phosphorylation by various protein kinases, but the possible role of protein kinase A (PKA) has not been investigated so far, and efficient compounds able to protect the endothelium from irradiation effects are needed. Here we report the beneficial effects of the PKA inhibitor KT5720 on a panel of irradiation-induced endothelial dysfunctions in human pulmonary microvascular endothelial cells (HPMECs). High-dose X-irradiation (15 Gy) triggered the late apoptosis of HPMECs independent of the ceramide/P38 MAP kinase pathway or p53. In contrast, the treatment of HPMECs with KT5720 completely prevented irradiation-induced apoptosis, whether applied before or after cell irradiation. Immunostainings of irradiated monolayers revealed that KT5720 treatment preserved the overall integrity of endothelial monolayers and adherens junctions linking endothelial cells. Real-time impedance measurements performed in HPMEC monolayers confirmed the overall protective role of KT5720 against irradiation. Treatment with KT5720 before or after irradiation also reduced irradiation-induced ICAM-1 overexpression. Finally, the possible role for PKA in the development of endothelial dysfunctions is discussed, but the potency of KT5720 to inhibit the development of a panel of irradiation-induced endothelial dysfunctions, whether applied before or after irradiation, suggests that this compound could be of great interest for both the prevention and treatment of vascular damages in the event of exposure to a high dose of radiation.

Generation of streptocarbazoles with cytotoxicities by pathway engineering and insights into their biosynthesis.

Streptocarbazoles are a class of indolocarbazole (ICZ) compounds produced by Streptomyces strains that feature unique cyclic N-glycosidic linkages between the 1,3-carbon atoms of the glycosyl moiety and the two indole nitrogen atoms. Although several streptocarbazole compounds display effective cytotoxic activity, their biosynthesis remains unclear. Herein, through the inactivation of the aminotransferase gene spcI in the staurosporine biosynthetic gene cluster spc followed by heterologous expression, two new streptocarbazole derivatives (1 and 3) and three known ICZs (2, 4, and 5) were generated. Their structures were determined by a combination of spectroscopic methods, circular dichroism measurements, and single-crystal X-ray diffraction. Compounds 1-4 displayed moderate cytotoxicity against HCT-116 cell line, and compounds 3 and 4 were effective against Huh 7 cell line. Double-gene knockout experiments allowed us to propose a biosynthetic pathway for streptocarbazole productions. Furthermore, by overexpression of the involving key enzymes, the production of streptocarbazoles 1 and 3 were improved by approximately 1.5-2.5 fold. IMPORTANCE: Indolocarbazoles (ICZs) are a group of antitumor agents, with several analogs used in clinical trials. Therefore, the identification of novel ICZ compounds is important for drug discovery. Streptocarbazoles harbor unique N-glycosidic linkages (N13-C1' and N12-C3'), distinguishing them from the representative ICZ compound staurosporine; however, their biosynthesis remains unclear. In this study, two new streptocarbazoles (1 and 3) with cytotoxic activities were obtained by manipulating the staurosporine biosynthetic gene cluster spc followed by heterologous expression. The biosynthetic pathway of streptocarbazoles was proposed, and their productions were improved through the overexpression of the key enzymes involved. This study enriches the structural diversity of ICZ compounds and would facilitate the discovery of new streptocarbazoles via synthetic biological strategies.

Response of a Novel KANK1::ALK Fusion to Alectinib in an Advanced Lung Adenocarcinoma: A Case Report.

More than 90 distinct fusion partners of ALK rearrangement have been identified. Different ALK fusions may exhibit different sensitivities to ALK tyrosine kinase inhibitors. The emergence of rare fusions poses significant challenges to targeted therapies. This study aimed to investigate the response of KANK1::ALK fusion to alectinib in an advanced lung adenocarcinoma. A novel KANK1::ALK fusion was identified by next-generation sequencing (NGS) and Ventana immunohistochemistry assessments. A 73-year-old woman who had never smoked was admitted with hemoptysis in May 2020. PET/CT revealed a nodule in the left upper lobe, with bilateral pulmonary and multiple lymph node metastases. The upper lobe nodule of the left lung was diagnosed as adenocarcinoma through bronchofiberscopy biopsy, resulting in a clinical diagnosis of stage IVA (cT1c,N3,M1a). Because the biopsy tissue was insufficient for NGS analysis, a blood-based genetic analysis was performed, revealing the presence of KRAS p.Q61R mutations. The patient received carboplatin and pemetrexed with pembrolizumab as first-line therapy, followed by maintenance therapy of pembrolizumab monotherapy. Although the tumor initially showed significant shrinkage, it unfortunately progressed further after 11 months. Subsequently, the patient was given carboplatin and pemetrexed with pembrolizumab again, but the tumor progression continued. An NGS using a rebiopsy of the left upper lobe tumor suggested a KANK1::ALK fusion. Alectinib was prescribed in January 2022, and a durable partial response was observed after 18 months. ALK rearrangements were observed in the broader spectrum of lung cancers. This study provided a potential treatment option for patients with KANK1::ALK fusions. Further studies are needed to understand the function of these fusions.

Chronic exposure to 3,6-dichlorocarbazole exacerbates non-alcoholic fatty liver disease in zebrafish by disrupting lipid metabolism and inducing special lipid biomarker accumulation.

Most previous studies have focused primarily on the adverse effects of environmental chemicals on organisms of good healthy. Although global prevalence of non-alcoholic fatty liver disease (NAFLD) has reached approximately 25%, the impact of environmentally persistent organic chemicals on organisms with NAFLD is substantially unknown. Polyhalogenated carbazoles (PHCZs) as emerging contaminants have been frequently detected in the environment and organisms. In this study, we investigated the impact of the most frequently detected PHCZs, 3,6-dichlorocarbazole (36-CCZ), on zebrafish with high-fat diet (HFD)-induced NAFLD. After 4 weeks exposure to environmentally relevant concentrations of 36-CCZ (0.16-0.45 µg/L), the accumulation of lipid in zebrafish liver dramatically increased, and the transcription of genes involved in lipid synthesis, transport and oxidation was significantly upregulated, demonstrating that 36-CCZ had exacerbated the NAFLD in zebrafish. Lipidomic analysis indicated that 36-CCZ had significantly affected liver lipid metabolic pathways, mainly including glycerolipids and glycerophospholipids. Additionally, fifteen lipids were identified as potential lipid biomarkers for 36-CCZ exacerbation of NAFLD, including diacylglycerols (DGs), triglycerides (TGs), phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), phosphatidic acid (PA), and phosphatidylinositol (PI). These findings demonstrate that long-term exposure to 36-CCZ can promote the progression of NAFLD, which will contribute to raising awareness of the health risks of PHCZs.

Occurrence, distribution, and ecological risks of polyhalogenated carbazoles in sediments from Daya Bay and Pearl River Estuary, China.

Polyhalogenated carbazoles (PHCZs) are a group of emerging organic pollutants attracting increasing concern. In this study, 32 sediment samples were collected from the Pearl River Estuary (PRE) and adjacent Daya Bay (DYB) in China and were investigated for the occurrence and distribution of PHCZs. Total concentration of sedimentary PHCZs (∑PHCZs) ranged from 0.79 to 3.08 ng/g in PRE and 0.89 to 1.95 ng/g in DYB, both containing 3,6-dichlorocarbazole as the main component. Higher concentrations of ∑PHCZs were found in the rivers-mouth and inner part of the PRE indicating their main origins from anthropogenic activities. Notably, concentrations of brominated carbazoles (BCZs) gradually increased offshore, which suggests the potential bio-transformation of BCZs under a saline environment. The toxic equivalent of PHCZs was estimated at 0.13-0.34 pg TEQ/g suggesting limited dioxin-like effects on local organisms.

Inflammatory cell death PANoptosis is induced by the anti-cancer curaxin CBL0137 via eliciting the assembly of ZBP1-associated PANoptosome.

OBJECTIVE: PANoptosis, a new form of regulated cell death, concomitantly manifests hallmarks for pyroptosis, apoptosis, and necroptosis. It has been usually observed in macrophages, a class of widely distributed innate immune cells in various tissues, upon pathogenic infections. The second-generation curaxin, CBL0137, can trigger necroptosis and apoptosis in cancer-associated fibroblasts. This study aimed to explore whether CBL0137 induces PANoptosis in macrophages in vitro and in mouse tissues in vivo. METHODS: Bone marrow-derived macrophages and J774A.1 cells were treated with CBL0137 or its combination with LPS for indicated time periods. Cell death was assayed by propidium iodide staining and immunoblotting. Immunofluorescence microscopy was used to detect cellular protein distribution. Mice were administered with CBL0137 plus LPS and their serum and tissues were collected for biochemical and histopathological analyses, respectively. RESULTS: The results showed that CBL0137 alone or in combination with LPS induced time- and dose-dependent cell death in macrophages, which was inhibited by a combination of multiple forms of cell death inhibitors but not each alone. This cell death was independent of NLRP3 expression. CBL0137 or CBL0137 + LPS-induced cell death was characterized by simultaneously increased hallmarks for pyroptosis, apoptosis and necroptosis, indicating that this is PANoptosis. Induction of PANoptosis was associated with Z-DNA formation in the nucleus and likely assembly of PANoptosome. ZBP1 was critical in mediating CBL0137 + LPS-induced cell death likely by sensing Z-DNA. Moreover, intraperitoneal administration of CBL0137 plus LPS induced systemic inflammatory responses and caused multi-organ (including the liver, kidney and lung) injury in mice due to induction of PANoptosis in these organs. CONCLUSIONS: CBL0137 alone or plus inflammatory stimulation induces PANoptosis both in vitro and in vivo, which is associated with systemic inflammatory responses in mice.

Combined toxic effects of polystyrene microplastics and 3,6-dibromocarbazole on zebrafish (Danio rerio) embryos.

Microplastics (MPs) and polyhalogenated carbazoles (PHCZs) are widely detected in the aquatic environment, and their ecological risks have become a research focus. Although there is an extensive co-distribution of MPs and PHCZs, their combined toxicity to aquatic organisms is still unclear. This study investigated the toxic effects of polystyrene microplastics (PS-MPs) and 3,6-dibromocarbazole (3,6-DBCZ) on zebrafish embryos by individual/combined exposure. This study showed that individual or combined exposure of PS-MPs (10 mg/L) and 3,6-DBCZ (0.5 mg/L) could significantly increase the rate of zebrafish embryo deformity, whereas no significant effect was observed on mortality and hatching rate. Furthermore, exposure to 3,6-DBCZ or PS-MPs increased reactive oxygen species (ROS) levels in zebrafish embryos, and the resulting oxidative stress induced apoptosis. Comparably, the levels of oxidative stress and apoptosis in zebrafish embryos were significantly reduced with the combined exposure of 3,6-DBCZ and PS-MPs. These observations suggest that the combined exposure of 3,6-DBCZ and PS-MPs has an antagonistic effect on oxidative stress and apoptosis. Fluorescence PS-MPs tracing and 3,6-DBCZ enrichment analysis showed that, with the protection of chorion, the entry of PS-MPs (5 and 50 µm) into the embryonic stage (55 hpf) of zebrafish was prevented. Moreover, after exposure for 96-144 hpf, PS-MPs served as a carrier to promote the 3,6-DBCZ accumulation and its dioxin-like toxicity in zebrafish larvae through ingestion. Compared with 5-µm PS-MPs, 50-µm PS-MPs promoted higher accumulation and dioxin-like toxicity of 3,6-DBCZ in zebrafish larvae. These findings provide that MPs can be used as an important carrier of PHCZs, influencing their toxicity and bioaccumulation in the organisms.