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Purpose: The synergistic effects of combining arsenic compounds with imatinib against chronic myeloid leukemia (CML) have been established using in vitro data. We conducted a clinical trial to compare the efficacy of the arsenic realgar-indigo naturalis formula (RIF) plus imatinib with that of imatinib monotherapy in patients with newly diagnosed chronic phase CML (CP-CML)., Methods: In this multicenter, randomized, double-blind, phase 3 trial, 191 outpatients with newly diagnosed CP-CML were randomly assigned to receive oral RIF plus imatinib (n = 96) or placebo plus imatinib (n = 95). The primary end point was the major molecular response (MMR) at 6 months. Secondary end points include molecular response 4 (MR 4 ), molecular response 4.5 (MR 4.5 ), progression-free survival (PFS), overall survival (OS), and adverse events., Results: The median follow-up duration was 51 months. Due to the COVID-19 pandemic, the recruitment to this study had to be terminated early, on May 28, 2020. The rates of MMR had no significant statistical difference between combination and imatinib arms at 6 months and any other time during the trial. MR 4 rates were similar in both arms. However, the 12-month cumulative rates of MR 4.5 in the combination and imatinib arms were 20.8% and 10.5%, respectively (p = 0.043). In core treatment since the 2-year analysis, the frequency of MR 4.5 was 55.6% in the combination arm and 38.6% in the imatinib arm (p = 0.063). PFS and OS were similar at five years. The safety profiles were similar and serious adverse events were uncommon in both groups., Conclusion: The results of imatinib plus RIF as a first-line treatment of CP-CML compared with imatinib might be more effective for achieving a deeper molecular response (Chinadrugtrials number, CTR20170221)., (© 2024. The Author(s).)

Aims: Trastuzumab, the first humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (ERBB2/HER2), is currently used as a first-line treatment for HER2 (+) tumours. However, trastuzumab increases the risk of cardiac complications without affecting myocardial structure, suggesting a distinct mechanism of cardiotoxicity., Methods and Results: We used medium from trastuzumab-treated human umbilical vein endothelial cells (HUVECs) to treat CCC-HEH-2 cells, the human embryonic cardiac tissue-derived cell lines, and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to assess the crosstalk between vascular endothelial cells (VECs) and cardiomyocytes. Protein mass spectrometry analysis was used to identify the key factors from VECs that regulate the function of cardiomyocytes. We applied RNA-sequencing to clarify the mechanism, by which PTX3 causes cardiac dysfunction. We used an anti-human/rat HER2 (neu) monoclonal antibody to generate a rat model that was used to evaluate the effects of trastuzumab on cardiac structure and function and the rescue effects of lapatinib on trastuzumab-induced cardiac side effects. Medium from trastuzumab-treated HUVECs apparently impaired the contractility of CCC-HEH-2 cells and iPSC-CMs. PTX3 from VECs caused defective cardiomyocyte contractility and cardiac dysfunction in mice, phenocopying trastuzumab treatment. PTX3 affected calcium homoeostasis in cardiomyocytes, which led to defective contractile properties. EGFR/STAT3 signalling in VECs contributed to the increased expression and release of PTX3. Notably, lapatinib, a dual inhibitor of EGFR/HER2, could rescue the cardiac complications caused by trastuzumab by blocking the release of PTX3., Conclusion: We identified a distinct mode of cardiotoxicity, wherein the activation of EGFR/STAT3 signalling by trastuzumab in VECs promotes PTX3 excretion, which contributes to the impaired contractility of cardiomyocytes by inhibiting cellular calcium signalling. We confirmed that lapatinib could be a feasible preventive agent against trastuzumab-induced cardiac complications and provided the rationale for the combined application of lapatinib and trastuzumab in cancer therapy., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: To compare the efficacy and safety of high-dose vitamin C plus FOLFOX ± bevacizumab versus FOLFOX ± bevacizumab as first-line treatment in patients with metastatic colorectal cancer (mCRC)., Patients and Methods: Between 2017 and 2019, histologically confirmed patients with mCRC (n = 442) with normal glucose-6-phosphate dehydrogenase status and no prior treatment for metastatic disease were randomized (1:1) into a control (FOLFOX ± bevacizumab) and an experimental [high-dose vitamin C (1.5 g/kg/d, intravenously for 3 hours from D1 to D3) plus FOLFOX ± bevacizumab] group. Randomization was based on the primary tumor location and bevacizumab prescription., Results: The progression-free survival (PFS) of the experimental group was not superior to the control group [median PFS, 8.6 vs. 8.3 months; HR, 0.86; 95% confidence interval (CI), 0.70-1.05; P = 0.1]. The objective response rate (ORR) and overall survival (OS) of the experimental and control groups were similar (ORR, 44.3% vs. 42.1%; P = 0.9; median OS, 20.7 vs. 19.7 months; P = 0.7). Grade 3 or higher treatment-related adverse events occurred in 33.5% and 30.3% of patients in the experimental and control groups, respectively. In prespecified subgroup analyses, patients with RAS mutation had significantly longer PFS (median PFS, 9.2 vs. 7.8 months; HR, 0.67; 95% CI, 0.50-0.91; P = 0.01) with vitamin C added to chemotherapy than with chemotherapy only., Conclusions: High-dose vitamin C plus chemotherapy failed to show superior PFS compared with chemotherapy in patients with mCRC as first-line treatment but may be beneficial in patients with mCRC harboring RAS mutation., (©2022 The Authors; Published by the American Association for Cancer Research.)

Cancers are immunologically heterogeneous. A range of immunotherapies target abnormal tumor immunity via different mechanisms of actions (MOAs), particularly various tumor-infiltrate leukocytes (TILs). We modeled loss of function (LOF) in four common anti-PD-1 antibody-responsive syngeneic tumors, MC38, Hepa1-6, CT-26 and EMT-6, by systematical depleting a series of TIL lineages to explore the mechanisms of tumor immunity and treatment. CD8 + -T-cells, CD4 + -T-cells, T reg , NK cells and macrophages were individually depleted through either direct administration of anti-marker antibodies/reagents or using DTR (diphtheria toxin receptor) knock-in mice, for some syngeneic tumors, where specific subsets were depleted following diphtheria toxin (DT) administration. These LOF experiments revealed distinctive intrinsic tumor immunity and thus different MOAs in their responses to anti-PD-1 antibody among different syngeneic tumors. Specifically, the intrinsic tumor immunity and the associated anti-PD-1 MOA were predominately driven by CD8 + cytotoxic TILs (CTL) in all syngeneic tumors, excluding Hepa1-6 where CD4 + T eff TILs played a key role. TIL-T reg also played a critical role in supporting tumor growth in all four syngeneic models as well as M 2 -macrophages. Pathway analysis using pharmacodynamic readouts of immuno-genomics and proteomics on MC38 and Hepa1-6 also revealed defined, but distinctive, immune pathways of activation and suppression between the two, closely associated with the efficacy and consistent with TIL-pharmacodynamic readouts. Understanding tumor immune-pathogenesis and treatment MOAs in the different syngeneic animal models, not only assists the selection of the right model for evaluating new immunotherapy of a given MOA, but also can potentially help to understand the potential disease mechanisms and strategize optimal immune-therapies in patients., (© 2022. The Author(s).)

Importance: The prevention of chemotherapy-induced nausea and vomiting has an important role in the overall management of cancer treatment., Objective: To evaluate whether adding aprepitant to palonosetron and dexamethasone can further prevent the incidence and severity of nausea and vomiting caused by FOLFIRI (fluorouracil, leucovorin, and irinotecan) or FOLFOX (fluorouracil, leucovorin, and oxaliplatin) chemotherapy regimens among women with gastrointestinal cancer at higher risk., Design, Setting, and Participants: This phase 3, double-blind, placebo-controlled randomized clinical trial recruited young women (age ≤50 years) who drank little or no alcohol and had gastrointestinal cancer for which they received FOLFOX or FOLFIRI chemotherapy. A total of 248 women were enrolled and assigned in the ratio 1:1 to intervention and control groups from August 4, 2015, to March 31, 2020. Intention-to-treat analysis was used to evaluate patient baseline characteristics and efficacy. The analysis was conducted on October 30, 2020., Interventions: Patients were randomly assigned to the aprepitant group (aprepitant, 125 mg, orally 60 minutes before initiation of chemotherapy on day 1 and 80 mg orally each morning of days 2 and 3; palonosetron, 0.25 mg, intravenously; and dexamethasone, 6 mg, orally 30 minutes before chemotherapy initiation on day 1) or the placebo group (placebo, 125 mg, orally 60 minutes before initiation of chemotherapy on day 1 and 80 mg orally on each morning of days 2 and 3; palonosetron, 0.25 mg, intravenously; and dexamethasone, 12 mg, orally 30 minutes before chemotherapy initiation on day 1)., Main Outcomes and Measures: The primary end point was the complete response (CR) rate, defined as the proportion of patients without emesis episodes or rescue medication use during the overall phase of the first cycle. Other efficacy indicators, such as no vomiting and no nausea, were measured as the secondary and exploratory end points., Results: A total of 248 women from 4 clinical centers in China entered this study, and 243 patients (aprepitant regimen, 125 patients [51.4%]; placebo regimen, 118 patients [48.5%]) were evaluable for efficacy and safety; mean (SD) age of the total population was 40.1 (7.3) years. The CR rate was significantly higher in the aprepitant group vs the control group overall (107 [87.0%] vs 80 [66.7%]; P < .001) and in the acute (114 [92.7%] vs 91 [75.8%]; P = .001) and delayed (109 [88.6%] vs 84 [70.0%]; P = .001) phases of the trial. The incidence of adverse events was similar between the 2 groups (100 [80.0%] vs 96 [81.3%]; P = .79), and no grade 3 or 4 aprepitant treatment-related adverse events were observed. Multivariable analysis revealed that aprepitant use was the only independent factor associated with CR during the overall phase., Conclusions and Relevance: The combination of aprepitant with palonosetron and dexamethasone provided increased antiemetic efficacy in the FOLFOX or FOLFIRI chemotherapy regimen and was well tolerated by younger women with gastrointestinal cancer who have a history of little or no alcohol consumption., Trial Registration: ClinicalTrials.gov Identifier: NCT03674294.

Resveratrol is a natural phytoestrogen produced by plants to protect themselves from injury, UV irradiation, and fungal attack. The main active structure is E-resveratrol, which has many pharmacological activities. As the structure of resveratrol is similar to the natural estrogen 17β-estradiol and the synthetic estrogen E-diethylstilbestrol, resveratrol is used in reducing the incidence of breast cancer. However, the therapeutic application of resveratrol is limited due to its low bioavailability. To improve its bioavailability and pharmacological activity, some resveratrol derivatives have been designed and synthesized by substitutions of methoxy, hydroxyl, and other functional groups or heterocyclic esterification either on the "A" or "B" ring, and double bonds were replaced by imine bonds and isometric heterocycles such as naphthyl and imidazole, or synthetic resveratrol oligomers. The structures, synthetic routes, and evaluation of the biological activities of these compounds are discussed. These are aimed at providing some references for the study of resveratrol derivatives in anti-breast cancer treatment., (© 2020 Deutsche Pharmazeutische Gesellschaft.)

(1) Background: Epithelial-mesenchymal transition (EMT) is an essential step for cancer metastasis; targeting EMT is an important path for cancer treatment and drug development. NF-κB, an important transcription factor, has been shown to be responsible for cancer metastasis by enhancing the EMT process. Our previous studies showed that (20S)Ginsenoside Rh2 (G-Rh2) inhibits NF-κB activity by targeting Anxa2, but it is still not known whether this targeted inhibition of NF-κB can inhibit the EMT process. (2) Methods: In vivo (20S)G-Rh2-Anxa2 interaction was assessed by cellular thermal shift assay. Protein interaction was determined by immuno-precipitation analysis. NF-κB activity was determined by dual luciferase reporter assay. Gene expression was determined by RT-PCR and immuno-blot. EMT was evaluated by wound healing and Transwell assay and EMT regulating gene expression. (3) Results: Anxa2 interacted with the NF-κB p50 subunit, promoted NF-κB activation, then accelerated mesenchymal-like gene expression and enhanced cell motility; all these cellular processes were inhibited by (20S)G-Rh2. In contrast, these (20S)G-Rh2 effect were completely eliminated by overexpression of Anxa2-K301A, an (20S)G-Rh2-binding-deficient mutant of Anxa2. (4) Conclusion: (20S)G-Rh2 inhibited NF-κB activation and related EMT by targeting Anxa2 in MDA-MB-231 cells.

Background: Small-cell lung cancer (SCLC) remains an aggressive cancer with short-term survival due to limited therapeutic options. Apatinib is a small-molecule tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptor-2. This study aimed to investigate the efficacy and safety of apatinib in patients with extensive-stage (EC) SCLC who had progressed after two or three previous therapies., Methods: Eligible patients were histologically confirmed ES-SCLC after two or three previous treatments, including a platinum-based regimen. Patients received apatinib at an initial dose of 500 mg once daily. The primary endpoint was the objective response rate., Results: Forty patients were enrolled. At the data cut-off time (November 15, 2018), the median follow-up was 7.4 months; no patients remained on treatment, and five were still in follow-up. An objective response was achieved in 7 of 40 patients (17.5%) in the intention-to-treat population, and 7 of 38 patients (18.4%) in the per-protocol population. The median progression-free survival and overall survival were 3.0 months and 5·8 months, respectively. The most commonly observed grade 3 or greater treatment-related adverse events were hypertension, hand-foot syndrome, increased L-gamma-glutamyltransferase., Conclusions: Apatinib exhibited efficacy and an acceptable safety profile in previously heavily-treated ES-SCLC patients. Further exploration of apatinib in phase III trials is warranted., Trial Registration: NCT02945852.

Purpose: Anaplastic lymphoma kinase (ALK) is now a validated kinase target in non-small cell lung cancer (NSCLC). We implemented three ALK laboratory methodologies: fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) and next-generation sequencing (NGS) to detect EML4-ALK fusions and compared the predictive value for Crizotinib efficacy in ALK-positive patients., Methods: 55 ALK positive patients confirmed by at least one method were enrolled in the present study, of whom 45 cases were assessed by FISH, IHC and NGS concurrently, and another 10 cases only received IHC and NGS assessment for ALK status., Results: IHC presented the uppermost positive rate (94.5%), followed by NGS (92.7%) and FISH(82.4%), among which IHC and NGS had the highest concordance rate of 87.3%. No difference was detected in ORR, DCR and PFS of ALK positive cases defined in three groups. Notably, NGS positive patients were correlated with a higher DCR and longer PFS compared to NGS negative cases (P = 0.02 and P = 0.09), while FISH and IHC status were not distinguishing in predicting the outcome of Crizotinib. TP53 concurrent mutation might reduce responsiveness to Crizotinib and worsen prognosis in ALK-rearranged NSCLC., Conclusion: FISH present a certain false-negative rate although considered the gold standard. Ventana-D5F3 IHC is qualified as a screening tool, while NGS positive may predict clinical benefit of Crizotinib more accurately, allowing efficient test for specific variants and concurrent genomic alterations., (Copyright © 2019. Published by Elsevier B.V.)

Immune checkpoint blockade-based immunotherapy is a new modality of cancer treatment with a unique mechanism that has gained increased numbers of indication and is now used in several cancer types. However, immune-related adverse events (irAEs) emerge as a new entity of diseases involving one or multiple organ systems. irAEs could result in interruption of immunotherapy, morbidities or even death. Among various manifestations of irAEs, immune-mediated hypophysitis is rare but important, requiring prompt diagnosis and treatment to avoid life-threatening conditions. We report seven cases of immune-mediated hypophysitis in Taiwan. They suffered from various types of advanced cancer and received different regimens of immune checkpoint inhibitors. The time of onset after initiation of immunotherapy ranged from 5 to 36 weeks. All seven subjects were diagnosed of central adrenal insufficiency, while four of them had primary hypothyroidism. There was no typical finding of infiltrative hypophysitis on the pituitary MRI. There was no documented hormone recovery after diagnosis of hypophysitis, and the tumor responses to immunotherapy were variable in these seven patients. In conclusion, immune-mediated hypophysitis is often irreversible. Fortunately, it can be managed adequately with hormone replacements. Further investigations are warranted to unveil underlying mechanisms and ethnic differences to guide the solutions., (Copyright © 2018. Published by Elsevier B.V.)

Dasatinib shows remarkable activity against imatinib-refractory chronic myelogenous leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL). However, severe cardiovascular toxicity limits the clinical applications of dasatinib. Since the underlying mechanism of dasatinib-induced cardiotoxicity is still elusive, we aim to clarify this. Recent studies have shown that necroptosis and apoptosis participate in multiple toxicity development. Here, we first report that dasatinib could directly induce cardiomyocytes death, as analyzed by the Sulforhodamine B (SRB) assay. This type of cardiomyocytes death was mediated by the necrosis pathway rather than apoptosis, as determined by using flow cytometry to characterize the mode of dasatinib-induced cell death. Inhibition of receptor-interacting protein kinase 1 (RIP1)activity and knockdown of receptor-interacting protein kinase 3 (RIP3)expression can block dasatinib-evoked cardiotoxicity, which further confirmed the involvement of necroptosis. We next found that the classic substrates of RIP3, mixed lineage kinase domain-like protein (MLKL) and Ca 2+ -calmodulin-dependent protein kinase II (CaMKII) were not involved in dasatinib-induced cardiomyocytes necroptosis. What's more, unlike the inflammation-associated necroptosis, dasatinib-triggered necroptosis was dependent on intracellular instead of secreted High-mobility group box 1 (HMGB1) protein. Collectively, our study revealed that dasatinib-induced cardiotoxicity acted via leading cardiomyocytes to HMGB1-mediated necroptosis, indicating a viable strategy for prevention of dasatinib-induced cardiotoxicity., (Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Increasing evidence leads to a ratiocination that genetic heterogeneity of the lung adenocarcinoma with EGFR mutations may impact clinical responses and outcomes to EGFR tyrosine kinase inhibitor (TKI) treatments., Methods: We performed genetic profiling of pre-treatment samples of 69 lung adenocarcinoma patients, including tumor FFPE and cell-free DNA (cfDNA), targeting 416 cancer-related genes using next generation sequencing. We analyzed mutation concordance across sample types and investigated potential mechanisms that confer primary resistance to EGFR-TKIs in patients with short progression-free survival (PFS) versus those with long PFS., Results: We detected a total of 200 actionable genetic alterations (mean: 2.9 variants/patient, range: 1-7 variants) in tumor FFPE and 140 actionable genetic alterations (mean: 2.0 variants/patient, range: 0-5 variants) in matched cfDNA, respectively. All patients had EGFR TKI-sensitizing mutations, including EGFR Ex19del, L858R, G719S/C, and L861Q. Concurrent TP53 mutations were most commonly observed in 72.5% of patients, followed by EGFR amplification (20.3%), RB1 (10.1%), PIK3CA (7.2%), and MYC (5.8%). For EGFR activating mutations, the concordance rate was 88.2% between cfDNA and FFPE samples. Furthermore, we identified genes that potentially confer primary resistance to EGFR-TKIs including CDC73, SMAD4, RB1 and PIK3CA. We also report signaling pathways enriched in patients with TKI primary resistance., Conclusions: We note the genetic complexity and heterogeneity of EGFR-mutated lung adenocarcinoma and underscore that mutation status is highly concordant between tumor FFPE and cfDNA samples. This study also highlights the alterations that potentially confer primary resistance to EGFR TKI treatments in patients who demonstrated short PFS., (Copyright © 2018. Published by Elsevier B.V.)

Annexin A2, a multifunctional tumor associated protein, promotes nuclear factor-kappa B (NF-κB) activation by interacting with NF-κB p50 subunit and facilitating its nuclear translocation. Here we demonstrated that two ginsenosides Rg5 (G-Rg5) and Rk1 (G-Rk1), with similar structure, directly bound to Annexin A2 by molecular docking and cellular thermal shift assay. Both Rg5 and Rk1 inhibited the interaction between Annexin A2 and NF-κB p50 subunit, their translocation to nuclear and NF-κB activation. Inhibition of NF-κB by these two ginsenosides decreased the expression of inhibitor of apoptosis proteins (IAPs), leading to caspase activation and apoptosis. Over expression of K302A Annexin A2, a mutant version of Annexin A2, which fails to interact with G-Rg5 and G-Rk1, effectively reduced the NF-κB inhibitory effect and apoptosis induced by G-Rg5 and G-Rk1. In addition, the knockdown of Annexin A2 largely enhanced NF-κB activation and apoptosis induced by the two molecules, indicating that the effects of G-Rg5 and G-Rk1 on NF-κB were mainly mediated by Annexin A2. Taken together, this study for the first time demonstrated that G-Rg5 and G-Rk1 inhibit tumor cell growth by targeting Annexin A2 and NF-κB pathway, and G-Rg5 and G-Rk1 might be promising natural compounds for targeted cancer therapy.

Several vesicular systems loaded with curcumin have found their way in the therapeutic applications of several diseases, primarily acting through their immunological pathways. Such systems use particles at a nanoscale range, bringing about their intended use through a range of complex mechanisms. Apart from delivering drug substances into target tissues, these vesicular systems also effectively overcome problems like insolubility and unequal drug distribution. Several mechanisms are explored lately by different workers, and interest over vesicular curcumin has been renewed in the past decade. This commentary discusses several immunological targets in which curcumin is employed in a vesicular form.

Oral drug delivery has attracted substantial attention due to its advantages over other administration routes. Bacillus spores, as oral probiotic agents, are applied widely. In this paper, a novel Bacillus spore-based oral colon targeted carrier loading curcumin was developed for colon cancer treatment. Curcumin was linked covalently with the outer coat of Bacillus spore and folate, respectively (SPORE-CUR-FA). Bacillus spores are capable of delivering drugs to the colon area through gastric barrier, taking the advantage of its tolerance to the harsh conditions and disintegration of the outer coat of spores after germination in the colon. The drug release in vitro and in vivo of SPORE-CUR-FA was investigated. Results showed that SPORE-CUR-FA had the characteristics of colon-targeted drug release. Pharmacokinetic studies confirmed that Bacillus spore-based carriers could efficiently improve the oral bioavailability of curcumin. In vitro and in vivo anti-tumor studies showed that SPORE-CUR-FA had substantial ability for inhibiting colon cancer cells. These findings suggest that this Bacillus spore-based oral drug delivery system has a great potential for the treatment of colon cancer., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The 20S ginsenoside Rh2 (G-Rh2) effectively inhibits cancer cell growth and survival in both animal models and cell lines. However, its molecular targets and mechanism of action remain largely unknown. By screening for molecules that interact with (20S)G-Rh2 in a phage display assay, we have identified Annexin A2 as a potential target that mediates its anti-cancer activity. Isothermal titration calorimetry and a cellular thermal shift assay demonstrated that (20S)G-Rh2 directly bound to either recombinant or intracellular Annexin A2. This binding inhibited the interaction between Annexin A2 and the NF-кB p50 subunit, which attenuated the nuclear translocations of NF-кB p50 subunit and reduced the transactivation activity of NF-кB. Correspond to this result, (20S)G-Rh2 treatment significantly down-regulated the expression of IAPs (inhibitors of apoptosis), the well-established NF-кB targets that promote cell survival. Moreover, (20S)G-Rh2 synergized with Annexin A2 inactivation to promote apoptosis. Taken together, this study for the first time suggests a cellular target and a molecular pathway by which (20S)G-Rh2 inhibits cancer cell growth. As over-expression of Annexin A2 was evident in human hepatoma, (20S)G-Rh2 might be a promising natural compound for targeted liver cancer therapy.

An increasing number of studies reveal the significance of genetic markers in guiding target treatment and refining prognosis. This retrospective observational study aims to assess the mutation profile of metastatic colorectal cancer (mCRC) in Chinese population with the help of MassARRAY® technique platform and OncoCarta™ Panel.322 Chinese patients with mCRC who received clinical molecular testing as part of their standard care were investigated. 80 patients received cetuximab palliative treatment. 238 common hot-spot mutations of 19 cancer related genes in the OncoCarta™ Panel were tested.44 mutations in 11 genes were detected in 156 cases (48.4%). At least one mutation was identified in 38.5% (124/322) of all tested cases, two concomitant mutations in 9.0% (29/322) and three mutations in 3 cases (<1%). KRAS was the most frequently mutated gene (34.8%), followed by PIK3CA (9.6%), NRAS (4.3%), BRAF (3.4%), EGFR (2.5%) and HRAS (1.2%). Less frequent mutations were detected in PDGFRA, RET, AKT1, FGFR1, and ERBB2. Co-mutation of RAS family subtypes was observed in 5 patients, and KRAS and BRAF concurrent mutation in 1 patient. KRAS, NRAS, BRAF and PIK3CA mutations had association with some clinicopathological features statistically. Patients identified as wild-type in all 19 genes had better objective response rate when treated with cetuximab.The clinical molecular testing with OncoCarta™ Panel supplemented the limited data of mCRC in Chinese population, and offered a clearer landscape of multiple gene mutational profile in not only clinically prognostic KRAS, NRAS, BRAF and PIK3CA genes, but also less frequent mutated genes. Knowledge of these multiple gene mutation patterns may give clues in exploring interesting accompanying co-occurrence relationship or mutually exclusive relationship between mutated genes, as well as in predicting benefit of all-wild-type patients from anti-EGFR treatment., Competing Interests: All authors declared that there is no conflict of interest.

Anaplastic lymphoma kinase (ALK) is a highly attractive therapeutic target for the treatment of some non-small cell lung cancer patients. This Letter describes the further SAR exploration on the novel 3-sulfonylpyrazol-4-amino pyrimidine scaffold. This work identified a compound 53 with very good in vitro/in vivo efficacies, good DMPK properties together with better hERG tolerability and it is currently being profiled for the evaluation as a potential pre-clinical candidate., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aim: Hyperoside (quercetin-3-O-β-D-galactopyranoside) is a flavonol glycoside found in plants of the genera Hypericum and Crataegus, which exhibits anticancer, anti-oxidant, and anti-inflammatory activities. In this study we investigated whether autophagy was involved in the anticancer mechanisms of hyperoside in human non-small cell lung cancer cells in vitro., Methods: Human non-small cell lung cancer cell line A549 was tested, and human bronchial epithelial cell line BEAS-2B was used for comparison. The expression of LC3-II, apoptotic and signaling proteins was measured using Western blotting. Autophagosomes were observed with MDC staining, LC3 immunocytochemistry, and GFP-LC3 fusion protein techniques. Cell viability was assessed using MTT assay., Results: Hyperoside (0.5, 1, 2 mmol/L) dose-dependently increased the expression of LC3-II and autophagosome numbers in A549 cells, but had no such effects in BEAS-2B cells. Moreover, hyperoside dose-dependently inhibited the phosphorylation of Akt, mTOR, p70S6K and 4E-BP1, but increased the phosphorylation of ERK1/2 in A549 cells. Insulin (200 nmol/L) markedly enhanced the phosphorylation of Akt and decreased LC3-II expression in A549 cells, which were reversed by pretreatment with hyperoside, whereas the MEK1/2 inhibitor U0126 (20 μmol/L) did not blocked hyperoside-induced LC3-II expression. Finally, hyperoside dose-dependently suppressed the cell viability and induced apoptosis in A549 cells, which were significantly attenuated by pretreatment with the autophagy inhibitor 3-methyladenine (2.5 mmol/L)., Conclusion: Hyperoside induces both autophagy and apoptosis in human non-small cell lung cancer cells in vitro. The autophagy is induced through inhibiting the Akt/mTOR/p70S6K signal pathways, which contributes to anticancer actions of hyperoside.

Quercetin, a natural flavonoid, inhibits the growth of leukemia cells and induces apoptosis. Heat shock protein 27 (HSP27) has been reported to promote the development of leukemia by protecting tumor cells from apoptosis through various mechanisms. The present study investigated the effects of small hairpin (sh)RNA-mediated HSP27 knockdown on the anti‑cancer effects of quercetin in U937 human leukemia cells. Cells were transfected with recombinant lentiviral vector pCMV‑G‑NR‑U6‑shHSP27 (shHSP27), which expressed shRNA specifically targeting the HSP27 gene, alone or in combination with quercetin. The results showed that shHSP27 and quercetin synergistically inhibited U937 cell proliferation and induced apoptosis by decreasing the Bcl2-to-Bax ratio. Furthermore, this combined treatment significantly suppressed the infiltration of tumor cells and the expression of angiogenesis‑associated proteins HIF1α and VEGF. Compared with shHSP27 or quercetin alone, shHSP27 plus quercetin markedly decreased the protein expression of cyclinD1 and thus blocked the cell cycle at G1 phase. The Notch/AKT/mTOR signaling pathway is important in tumor aggressiveness; quercetin plus shHSP27 significantly decreased Notch 1 expression and the phosphorylation levels of the downstream signaling proteins AKT and mTOR. The inhibitory effects of quercetin plus shHSP27 on this pathway may thus have been responsible for the cell cycle arrest, inhibition of proliferations and infiltration as well as enhancement of apoptosis. Therefore, these findings collectively suggested that suppression of HSP27 expression amplified the anti‑cancer effects of quercetin in U937 human leukemia cells, and that quercetin in combination with shHSP27 represents a promising therapeutic strategy for human leukemia.

Tetrandrine (Tet), a bisbenzylisoquinoline alkaloid, has been reported to possess anti-tumour activity. However, its effects on human glioma remain unknown. In this study, we demonstrated that Tet inhibited human glioma cell growth in vitro and in vivo. It has been hypothesised that Tet inhibits glioma growth by affecting glioma cell survival, proliferation and vasculature in and around the xenograft tumour in the chick CAM model and signal transducer and activator of transcription 3 (STAT3) mediated these activities. Therefore, we conducted a detailed analysis of the inhibitory effects of Tet on cell survival using a TUNEL assay and flow cytometric analysis; on cell proliferation based on the expression of proliferating cell nuclear antigen; and on angiogenesis using a CAM anti-angiogenesis assay. We used western blotting to investigate the role of STAT3 on the anti-glioma activities of Tet. The results revealed that Tet inhibited survival and proliferation in human glioma cells, impaired tumour angiogenesis and decreased the expression of phosphorylated STAT3 and its downstream proteins. In sum, our data indicate that STAT3 is involved in Tet-induced the regression of glioma growth by activating tumour cell apoptosis, inhibiting glioma cell proliferation and inhibiting angiogenesis., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A new series of 2,4-diamino pyrimidine derivatives with a sulfone-substituted pyrazole right side-chain were discovered as potent anaplastic lymphoma kinase inhibitors. Structure-activity relationship of the left side-chain on phenyl substitutions were explored which delivered many potent ALK inhibitors. Among them, 29a showed favorable pharmacokinetic profiles in rats and dogs together with significant antitumor efficacy in EML4-ALK fusion xenograft model., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The new tuberculosis (TB) lead ecumicin (1), a cyclic tridecapeptide, was isolated from Nonomuraea sp. MJM5123, following a high-throughput campaign for anti-TB activity. The large molecular weight of 1599 amu detected by LC-HR-MS precluded the initial inference of its molecular formula. The individual building blocks were identified by extensive NMR experiments. The resulting two possible planar structures were distinguished by LC-MS(2). Determination of absolute configuration and unambiguous structural confirmation were carried out by X-ray crystallography and Marfey's analysis.

Purpose: The benefit of docetaxel-based therapy in the second-line treatment of advanced non-small cell lung cancer (NSCLC) is still unclear. The goal of this meta-analysis was to assess the efficacy and toxicity of docetaxel-based doublet compared with docetaxel alone for patients with advanced NSCLC who failed to improve with first-line treatment., Methods: Several databases were searched, including PubMed, Embase, and the Cochrane databases. The end points were overall survival, progression-free survival (PFS), objective response rate, disease control rate, and grade 3 or 4 adverse events. Data were extracted from the studies by 2 independent reviewers. The meta-analysis was performed by using Review Manager version 5.2. The pooled hazard ratio (HR) or odds ratio (OR) and 95% CIs were calculated by using fixed or random effects models depending on the heterogeneity of the included trials., Findings: Twelve eligible trials involving 2680 patients were identified. The intention-to-treatment analysis found that docetaxel-based therapy significantly improved overall survival (HR, 0.89 [95% CI, 0.83-0.96]; P < 0.01), PFS (HR, 0.79 [95% CI, 0.71-0.89]; P < 0.01), objective response rate (OR, 1.73 [95% CI, 1.37-2.18; P < 0.01), and disease control rate (OR, 1.30 [95% CI, 1.09-1.55]; P < 0.01). In addition, a subgroup analysis based on type of combined drug showed that there were significant improvement in PFS and overall survival in combining docetaxel with targeted therapy. In addition, a higher incidence of grade 3 or 4 diarrhea and thrombocytopenia was observed in docetaxel-based doublet therapy., Implications: Based on the available evidence, docetaxel-based doublet therapy seems superior to docetaxel monotherapy as a second-line treatment for advanced NSCLC. More studies should focus on combining docetaxel with targeted therapy to identify patients who will most likely benefit from the appropriate combination targeted therapy., (Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.)

Trastuzumab has been the standard treatment in first-line treatment of HER-2-positive advanced breast cancer (H2ABC). This study explored whether the delayed and repeated use of trastuzumab could influence overall survival (OS). A total of 128 patients with H2ABC who had received at least one line of trastuzumab-based regimens were included. The primary endpoint was OS defined as from the date of first diagnosis of H2ABC to death. The median OS of initiating trastuzumab in first-line group (n = 56), in the second-line group (n = 32), and the third- or more-line group (n = 40) was 40.6 m, 39.5 m, and 38 m, respectively (P = 0.867). For patients who had received over one line of trastuzumab (n = 46), the median OS was 44 m, and for those receiving only one line (n = 67), it was 27.6 m (P = 0.059). The delayed use of trastuzumab has no negative effect on the OS of patients with H2ABC. There is a trend of improved OS over the repeated use of trastuzumab.

Novel oxygen-incorporated SAHA (oxa-SAHA) analogues, in which oxygen was inserted in the alkyl linker connecting the hydroxamic acid moiety and amide group, were synthesized and their inhibitory activities on histone deacetylase were evaluated. The most active oxa-SAHA analogue potently inhibited histone deacetylase, almost as potently as SAHA. Various structural modifications in the amide, but not the hydroxamic acid, significantly affected the inhibitory activities of the derivatives. Based on the inhibitory data, the N-phenyl moiety of the amide turned to be a better modification site for enhancing the inhibitory activity.

Aim: To generate a monoclonal antibody (McAb) against cell surface F1F0 ATP synthase (ATPase) and observe its antitumoral activity on both human umbilical vein endothelial cells (HUVEC) and tumor cells., Methods: Hybridoma cells secreting McAb against ATPase were produced by polyethylene glycol-mediated fusions and screened by ELISA. The specificity of McAb was demonstrated by immunofluorescence and confocal imaging, as well as flow cytometry analysis. After the blockade of surface ATPase with McAb on HUVEC and human breast adenocarcinoma MDA-MB-231 cells, an ATP determination kit and CellTiter96 AQueous Assay (MTS) assay were used to detect the effect of the antibody on extracellular ATP modification and cell proliferation. A cellular cytotoxicity assay in combination with doxorubicin, and a cell migration assay on MDA-MB-231 cells were used to determine the antitumoral activity. Finally, a HUVEC tube formation assay was used to detect the antiangiogenic effect of McAb178-5G10., Results: A monoclonal antibody (McAb178-5G10) against the beta-subunit of ATPase was generated, and its reactivity toward HUVEC and tumor cells was studied. We demonstrate that McAb178-5G10 binds to ATPase at the cell surface, where it is able to inhibit ATP synthesis. This antibody also prevents the proliferation of HUVEC and MDA-MB-231 cells. Furthermore, McAb178-5G10 enhances the tumoricidal effects of doxorubicin (P<0.05), inhibits the migration of MDA-MB- 231 in transwell assays (P<0.01), and disrupts HUVEC tube formation on Matrigel (P<0.01)., Conclusion: McAb178-5G10 binds preferentially to cell surface ATPase, blocks ATP synthesis, and exhibits both antiangiogenic and antitumorigenic effects.

Insulin-like growth factor 1 receptor (IGF-1R) supports neuronal survival against a wide variety of insults. This includes tumor necrosis factor-alpha (TNFalpha)-mediated neuronal damage, which represents one of the factors suspected to play a role in HIV-associated dementia (HAD). PC12 neurons engineered to express human IGF-1R (PC12/IGF-1R) maintain neuronal processes on collagen IV for several weeks. However, prolonged treatment with TNFalpha caused degeneration of neuronal processes, with no apparent signs of apoptosis. In this process, TNFalpha did not affect IGF-1-mediated phosphorylation of IRS-1, IRS-2, Akt, or Erks. In addition, PC12/IGF-1R cells were found to express predominantly alpha1beta1 integrin, which has high affinity to collagen IV. The treatment of PC12/IGF-1R neurons with a specific alpha1beta1 integrin inhibitor, obtustatin, also caused loss of neuronal processes, accompanied by a quick cell detachment and extensive apoptosis. In the presence of IGF-1, both TNFalpha-induced and obtustatin-induced degeneration of neuronal processes were effectively inhibited. Furthermore, TNFalpha-mediated neuronal degeneration correlated with decreased attachment of PC12/IGF-1R cells to collagen IV and with a reduced level of alpha1beta1 integrin, consistent with a role for this surface protein in the maintenance of neuronal processes. Thus the neuroprotective effects of IGF-1 are not restricted to its antiapoptotic properties but also involve an additional neuroprotective mechanism, by which IGF-1 counteracts the negative effect of TNFalpha on alpha1beta1 integrin-mediated attachment to collagen IV.

In this study we show that panaxadiol, a ginseng saponin with a dammarane skeleton, induces apoptotic cell death by depolarization of mitochondrial membrane potential in human hepatoma SK-HEP-1 cells. Sequential activation of caspases-9, -3, and -7, but not of caspase-8, occurs after mitochondrial membrane depolarization and cytochrome c release from the mitochondria of panaxadiol-treated cells. Moreover, Cdk2 kinase activity, but not Cdc2 kinase activity, is markedly upregulated in the early stages of apoptosis. Olomoucine or roscovitine, specific Cdks inhibitors, effectively prevent mitochondrial membrane depolarization as well as apoptotic cell death in panaxadiol-treated cells. Thus, panaxadiol-treatment induces cell death-dependent activation of Cdk2 kinase activity, which is functionally associated with depolarization of mitochondrial membrane potential and subsequent cytochrome c release.

Background: Thymic epithelial tumors (TETs) are rare malignant tumors with limited treatment options. No established second‐line treatment regimen is available following the preferred first‐line chemotherapy, resulting in unsatisfactory efficacy and poor prognosis for patients with advanced TETs. This study aimed to evaluate the efficacy of small molecule multitarget antiangiogenic inhibitors as well as the prognostic factors for advanced TETs. Methods: A retrospective study was conducted using data from a real‐world database. Clinical information and survival follow‐up data were collected from 52 patients with advanced TETs who received small molecule multitarget antiangiogenic inhibitors at Zhejiang Cancer Hospital between August 10, 2016 and August 10, 2022. The short‐term efficacy of the treatments, survival time of the patients, and relevant prognostic factors of advanced TETs were analyzed. Results: Out of the 52 patients included in this study, 16 had thymoma and 36 had thymic carcinoma. The 52 patients had an overall response rate of 21.1% and a disease control rate of 94.2%. In addition, the median progression‐free survival (PFS) was 8.05 months, and the overall survival (OS) was 25.00 months. Apatinib was given to 33 patients, anlotinib to 15 patients, and sunitinib or lenvatinib to four patients. Only seven patients received antiangiogenic inhibitors as their first‐line therapy, 27 patients as their second‐line therapy, and 18 patients as third‐line or subsequent therapy. Meanwhile, 42 patients received monotherapy with an antiangiogenesis inhibitor, while 10 patients received combination therapy. Univariate analysis indicated that the combined treatment was associated with a superior OS (p = 0.044); multivariate analysis indicated that the combined treatment was an independent prognostic factor for PFS (p = 0.014) and OS (p = 0.012). Conclusion: The findings suggest that small molecule multitarget antiangiogenic inhibitors are efficacious as second or post‐line treatments as a viable alternative treatment option for patients with advanced TETs. [ABSTRACT FROM AUTHOR]

Six new polyoxygenated seco-cyclohexenes, artahongkongenes A–F ( 1–6 ), together with six known analogues ( 7–12 ) were isolated from the stems and leaves of Artabotrys hongkongensis . Their structures were elucidated by extensive spectroscopic methods. All new compounds were evaluated for their cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro . New seco-cyclohexenes 1–6 showed significant inhibitory effects against various human cancer cell lines with IC 50 values ranging from 0.26 to 16.58 μM. [ABSTRACT FROM AUTHOR]

Background: The first one-arm phase II trial aimed to evaluate and predict efficacy and safety of S-1 plus oral leucovorin (S-1/LV) as first-line chemotherapy for patients with advanced gastric cancer (AGC), using S-1 pharmacogenetic pathway approach.Patients and Methods: A total of 39 patients orally took S-1 at conventional dose and LV simultaneously at a dose of 25 mg twice daily for a week, within a 2-week cycle. The primary endpoint was overall response rate (ORR), while the secondary endpoints were progression-free survival (PFS), time to failure (TTF), overall survival (OS), disease control rate (DCR), and adverse events (AEs). Peripheral blood was sampled prospectively for baseline expression of dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), thymidine phosphorylase (TP), and thymidylate synthase (TS), CYP2A6 gene polymorphisms, and 5-FU pharmacokinetics.Results: The ORR and DCR were 41.0 and 76.9%. The median PFS, TTF, and OS were 4.13, 3.70, and 11.40 months. Grade 3-4 AEs occurred in only 13 patients, and grade 4 AEs occurred in only 1 of them. High OPRT/TS and peritoneal metastasis (vs. liver metastasis) independently predicted responding. High OPRT/DPD independently predicted grade 3-4 AEs. High AUC0-24h of 5-FU and metastatic/recurrent sites ≤2 (vs. >3) independently predicted prolonged PFS. Low baseline plasmic DPD independently predicted prolonged OS.Conclusions: Two-week, oral S-1/LV regimen demonstrated promising efficacy and safety as first-line chemotherapy for AGC. CLINICALTRIALS.Gov Identifier: NCT02090153. [ABSTRACT FROM AUTHOR]

Objective: To investigate the oncologic and reproductive outcomes after progestin treatment of complex endometrial hyperplasia (CEH) and grade 1 endometrial carcinoma (EC).Methods: In a retrospective study, data were obtained for patients aged 20-42years with CEH or grade 1 EC at presumed stage IA (without myometrial invasion) who wished to preserve fertility and were treated at the Peking Union Medical College Hospital, China, between January 1, 2000, and December 31, 2011. Patients had received oral medroxyprogesterone acetate (250-500mg/day) or megestrol acetate (160-480mg/day) for at least 6months. Response to progestin treatment was assessed histologically.Results: Among 53 included patients, 39 (74%) achieved complete response after a median period of 6 (3-24) months. Complete response was less frequent among obese than nonobese patients (4/12 [33%] vs 35/41 [85%]; P=0.001). Disease recurrence was recorded in 10 (26%) patients with complete response; the 5-year recurrence-free survival rate was 71%. Among the 33 patients who retained a desire to conceive, 17 (52%) became pregnant.Conclusion: Fertility-sparing management with oral progestin is effective. Obesity is associated with a lower probability of long-term success. [ABSTRACT FROM AUTHOR]

The novel compound JRS-15 was obtained through the chemical modification of xylocydine. JRS-15 exhibited much stronger cytotoxic and pro-apoptotic activity than its parent compound in various cancer cell lines, with IC50 values in HeLa, HepG2, SK-HEP-1, PC-3M and A549 cells ranging from 12.42 to 28.25 µM. In addition, it is more potent for killing cancer than non-cancerous cells. Mechanistic studies showed that JRS-15 treatment arrested cell cycle at the G1/S phase, which further triggered the translocation of Bax and Bak to the mitochondria, resulting in mitochondrial membrane potential (MMP) depolarization and the subsequent release of cytochrome c and the second mitochondria-derived activator of caspase (Smac). The sequential activation of caspase-9 and caspase-3/7 and the cleavage of poly (ADP-ribose) polymerase (PARP) were observed following these mitochondrial events. Caspase-8, an initiator caspase that is required to activate the membrane receptor-mediated extrinsic apoptosis pathway was not activated in JRS-15-treated cells. Further analysis showed that the levels of the anti-apoptotic proteins Bcl-xL and XIAP were significantly reduced upon JRS-15 treatment. Furthermore, the caspase-9 inhibitor z-LEHD-fmk, the pan-caspase inhibitor z-VAD-fmk, and Bcl-xL or XIAP overexpression all effectively prevented JRS-15-induced apoptosis. Taken together, these results indicate that JRS-15 induces cancer cell apoptosis by regulating multiple apoptosis-related proteins, and this compound may therefore be a good candidate reagent for anticancer therapy. [ABSTRACT FROM AUTHOR]

Gambogic acid (GA) is in a phase II clinical trial as an antitumor and antiangiogenesis agent. In this study, 36 GA derivatives were synthesized and screened in a zebrafish model to evaluate their antiangiogenic activity and toxicity. Derivatives 4, 32, 35, 36 effectively suppressed the formation of newly grown blood vessels and showed lower toxicities than GA as evaluated by zebrafish heart rates and mortalities. They also exhibited more potent migration and HUVEC tube formation inhibiting activities than GA. Among them, 36 was the most potent one, suggesting that it may serve as a potential new antiangiogenesis candidate with low toxicity. Additionally, 36 showed comparable antiproliferative activity to HUVECs and five tumor cell lines but low cytotoxicity to LO2 cells. [ABSTRACT FROM AUTHOR]

Purpose: Bone is the most common site of metastases from nasopharyngeal carcinoma (NPC). Zoledronic acid (ZA) used to prevent skeletal-related events (SREs) of bone metastases has shown anti-tumor effects; yet, no report has been found on the survival benefit of ZA in NPC. This study aimed to evaluate whether ZA can bring survival benefits to patients with bone metastases from NPC. Methods: A total of 307 patients with of NPC who had bone metastases were analyzed retrospectively. The differences of survival between patients treated with chemotherapy combined with ZA and those with chemotherapy alone were evaluated by the log-rank test. The Cox multivariate analyses of clinical features and different treatment methods of the 307 patients were conducted. Results: The prevalence of SREs in the combined approach group was lower than that with chemotherapy alone (34% vs. 48%, X = 7.003, P = 0.008). The combined approach group had better progression-free survival (PFS) (11.5 vs. 5.5 months, P < 0.001) and overall survival (OS) (23.5 vs. 17.5 months, P < 0.001) than chemotherapy alone group. Cox multivariate analysis identified the following independent prognostic factors: ZA treatment, bone metastatic sites, baseline serum alkaline phosphatase (ALP) level, SREs and cycles of chemotherapy. Conclusions: ZA treatment combined with chemotherapy could reduce SREs and improve PFS and OS for NPC patients with bone metastases. [ABSTRACT FROM AUTHOR]

Two novel γ -lactone derivatives, trigoheterophines A ( 1 ) and B ( 2 ), together with four known furan derivatives ( 3 – 6 ), were isolated from the stems and leaves of Trigonostemon heterophyllus . The structures of 1 and 2 were elucidated by extensive spectroscopic methods and the known compounds were identified by comparing with the data reported in literature. Among them, trigoheterophines A ( 1 ) and B ( 2 ) represent an unusual type of γ -lactone derivatives, possessing 21 carbon atoms on the carbon skeleton, and known compouds ( 3 – 6 ) are rare furan derivatives in the plant kingdom with diverse long-chain hydrocarbyl groups as substituents at C-4. All isolated compounds were evaluated for their antiproliferative activities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro . Compounds 1 – 6 showed significant antiproliferative effects against various human cancer cell lines with IC 50 values ranging from 0.28 to 12.06 μM. These findings suggest that the discoveries of these novel γ -lactone derivatives and furan derivatives with significant antiproliferative activities isolated from T. heterophyllus could be of great importance to the development of new anticancer agents. [ABSTRACT FROM AUTHOR]

Abstract: Anti-tumor activity of bakuchiol, an analogue of resveratrol, was investigated on human lung adenocarcinoma A549 cell line. MTT assay revealed that IC50 of bakuchiol at 72h was 9.58±1.12μmol/l, much lower than that of resveratrol (33.02±2.35μmol/l). Bakuchiol but not resveratrol elevated intracellular reactive oxygen species. Bakuchiol reduced mitochondrial membrane potential (∆Ψm) of cells in a concentration- and time-dependent manner, showing a more potent effect than that of resveratrol. More apoptotic cells were induced by bakuchiol, compared with resveratrol. Subsequently, S phase arrest, caspase 9/3 activaton, p53 and Bax up-regulation, as well as Bcl-2 down-regulation were observed in bakuchiol-treated A549 cells. The results point toward that S phase-related cell cycle regulation, more importantly reactive oxygen species-related apoptosis might contribute to the anticancer properties of bakuchiol, which will strongly support the further development of bakuchiol against non-small-cell lung cancer. [ABSTRACT FROM AUTHOR]