MitoCur-1 induces ferroptosis to reverse vemurafenib resistance in melanoma through inhibition of USP14.

Melanoma is an aggressive malignant tumor with a poor prognosis. Vemurafenib (PLX4032, vem) is applied to specifically treat BRAF V600E-mutated melanoma patients. However, prolonged usage of vem makes patients resistant to the drug and finally leads to clinical failure. We previously tested the combination regimen of tubulin inhibitor VERU-111 with vem, as well as USP14 selective inhibitor b-AP15 in combination with vem, both of which have showed profound therapeutic effects in overcoming vem resistance in vitro and in vivo. Most importantly, we discovered that vem-resistant melanoma cell lines highly expressed E3 ligase SKP2 and DUB enzyme USP14, and we have demonstrated that USP14 directly interacts and stabilizes SKP2, which contributes to vem resistance. These works give us a clue that USP14 might be a promising target to overcome vem resistance in melanoma. MitoCur-1 is a curcumin derivative, which was originally designed to specifically target tumor mitochondria inducing redox imbalance, thereby promoting tumor cell death. In this study, we have demonstrated that it can work as a novel USP14 inhibitor, and thus bears great potential in providing an anti-tumor effect and sensitizing vem-resistant cells by inducing ferroptosis in melanoma. Application of MitoCur-1 dramatically induces USP14 inhibition and inactivation of GPX4 enzyme, meanwhile, increases the depletion of GSH and decreases SLC7A11 expression level. As a result, ferrous iron-dependent lipid ROS accumulated in the cell, inducing ferroptosis, thus sensitizes the vem-resistant melanoma cell. Interestingly, overexpression of USP14 antagonized all the ferroptosis cascade events induced by MitoCur-1, therefore, we conclude that MitoCur-1 induces ferroptosis through inhibition of USP14. We believe that by inhibition of USP14, vem resistance can be reversed and will finally benefit melanoma patients in future.

Grouping motivational interviewing is only effective for younger patients with alcohol dependence in the rehabilitation stage.

Alcohol dependence (AD) is a risk factor for death and disability. Relapse prevention for AD has been exclusively dominated by psychotherapy intervention for many years. Our study aimed to investigate the efficacy of group motivational interviewing (MI) on the psychological craving for alcohol and depressive symptoms in AD patients in the rehabilitation phase, as well as the impact of age. The participants included 108 individuals with AD in the rehabilitation phase. All participants were assigned to the MI intervention group or the control group and were treated for 6 weeks. The severity of psychological craving for alcohol was assessed by the Penn Alcohol Craving Scale (PACS), and psychological status was evaluated by the Hamilton Depression Rating Scale (HAMD). We found that group MI significantly reduced the psychological craving for alcohol in patients with AD in the rehabilitation phase (p < 0.05). In addition, when patients were divided into two groups according to their ages, we found that group MI interventions tended to be effective only in younger patients with AD, but not in older patients. Our findings provide further evidence that the efficacy of group MI interventions was influenced by the age of patients with AD in the rehabilitation stage.

Dynamic functional thalamocortical dysconnectivity in schizophrenia correlates to antipsychotics response.

Although many studies have showed abnormal thalamocortical networks in patients with schizophrenia (SCZ), the dynamic functional thalamocortical connectivity of individuals with SCZ and the effect of antipsychotics on this connectivity have not been investigated. Drug-naïve first-episode individuals with SCZ and healthy controls were recruited. Patients were treated with risperidone for 12 weeks. Resting-state functional magnetic resonance imaging was acquired at baseline and week 12. We identified six functional thalamic subdivisions. The sliding window strategy was used to determine the dynamic functional connectivity (dFC) of each functional thalamic subdivision. Individuals with SCZ displayed decreased or increased dFC variance in different thalamic subdivisions. The baseline dFC between ventral posterior-lateral (VPL) portions and right dorsolateral superior frontal gyrus (rdSFG) correlated with psychotic symptoms. The dFC variance between VPL and right medial orbital superior frontal gyrus (rmoSFG) or rdSFG decreased after 12-week risperidone treatment. The decreased dFC variance between VPL and rmoSFG correlated with the reduction of PANSS scores. Interestingly, the dFC between VPL and rmoSFG or rdSFG decreased in responders. The dFC variance change of VPL and the averaged whole brain signal correlated with the risperidone efficacy. Our study demonstrates abnormal variability in thalamocortical dFC may be implicated in psychopathological symptoms and risperidone response in individuals with schizophrenia, suggesting that thalamocortical dFC variance may be correlated to the efficacy of antipsychotic treatment.Registration: ClinicalTrials.gov Identifier: NCT00435370. https://www.clinicaltrials.gov/ct2/show/NCT00435370?term=NCT00435370&draw=2&rank=1.

Tumor killing by a dietary curcumin mono-carbonyl analog that works as a selective ROS generator via TrxR inhibition.

In comparison with normal cells, cancer cells feature intrinsic oxidative stress, thereby being more vulnerable to further production of reactive oxygen species (ROS) by pro-oxidative anticancer agents (PAAs). However, PAAs also inevitably generate ROS in normal cells, resulting in their narrow therapeutic window and toxic side effects that greatly limit their clinical application. To develop PAAs that generate ROS selectively in cancer cells over in normal cells, we rationally designed three series of 21 dietary curcumin 5-carbon mono-carbonyl analogs differentiated by either placement of the cyclohexanone, piperidone, and methylpiperidone linkers, or introduction of electron-withdrawing trifluoromethyl and electron-donating methoxyl groups on its two aromatic rings in the ortho, meta, or para position to the linkers. From the designed molecules, 2c, characterized of the presence of the meta-CF3-substituted mode and the piperidone linker, was identified as a potent selective ROS-generating agent, allowing its ability to kill selectively human non-small cell lung cancer NCI-H460 (IC50 = 0.44 µM) over human normal lung MRC-5 cells with a selectivity index of 32.0. Additionally, it was more potent and selective than the conventional chemotherapeutic agents (5-fluorouracil and camptothecin) did. Mechanistical investigation reveals that by means of its Michael acceptor unit and structure characteristics as described above, 2c could covalently modify the Sec-498 residue of intracellular thioredoxin reductase (TrxR) to generate ROS selectively, resulting in ROS-dependent apoptosis and ferroptosis of NCI-H460 cells. Noticeably, 2c inhibited significantly the growth of NCI-H460 cell xenograft tumor in nude mice without obvious toxicity to liver and kidney. Together, this work highlights a practical strategy of targeting TrxR overexpressed in cancer cells to develop PAAs capable of generating ROS selectively, as evidenced by the example of 2c.

Inhibition of USP14 enhances anti-tumor effect in vemurafenib-resistant melanoma by regulation of Skp2.

BACKGROUND: The mutation of BRAF V600E often occurred in melanoma and results in tumorigenesis. BRAF mutation drives hyperactivation of the RAF-MAPK-ERK pathway. The acquired drug resistance upon prolonged use of BRAF inhibitors (such as vemurafenib) still remains the main obstacle. Previously, we have found that E3 ligase Skp2 over-expresses vemurafenib-resistant melanoma cells, and knockdown of Skp2 enhances the anti-tumor effect of vemurafenib. Interestingly, the literature has reported that the selective USP14/UCHL5 inhibitor b-AP15 displays great potential in melanoma therapy; however, the molecular mechanism still remains unknown. METHODS: In vitro, the effect of the combination regimen of vemurafenib (Vem, PLX4032) and b-AP15 on vem-sensitive and vem-resistant melanoma has been investigated by wound healing, colony formation, transwell invasion assay, flow cytometry, lysosome staining, and ROS detection. In vivo, the combination effect on vem-resistant melanoma has been evaluated with a nude mice xenograft tumor model. GST-pulldown and co-immunoprecipitation (co-IP) assays have been applied to investigate the interactions between USP14, UCHL5, and Skp2. Cycloheximide (CHX) assay and ubiquitination assays have been used to explore the effect of USP14 on Skp2 protein half-life and ubiquitination status. RESULTS: In the present study, we have revealed that repression of USP14 sensitizes vemurafenib resistance in melanoma through a previously unappreciated mechanism that USP14 but not UCHL5 stabilizes Skp2, blocking its ubiquitination. K119 on Skp2 is required for USP14-mediated deubiquitination and stabilization of Skp2. Furthermore, the mutated catalytic activity amino acid cysteine (C) 114 on USP14 abrogates stabilization of Skp2. Stabilization of Skp2 is required for USP14 to negatively regulate autophagy. The combination regimen of Skp2 inhibitor vemurafenib and USP14/UCHL5 inhibitor b-AP15 dramatically inhibits cell viability, migration, invasion, and colony formation in vemurafenib-sensitive and vemurafenib-resistant melanoma. Vemurafenib and b-AP15 hold cells in the S phase thus leading to apoptosis as well as the formation of the autophagic vacuole in vemurafenib-resistant SKMEL28 cells. The enhanced proliferation effect of USP14 and Skp2 is mainly due to a more effective reduction of cell apoptosis and autophagy. Further evaluation of various protein alterations has revealed that the increased expression of cleaved-PARP, LC3, and decreased Ki67 are more obvious in the combination of vemurafenib and b-AP15 treatment than those in single-drug treatment. Moreover, the co-treatment of vemurafenib and b-AP15 dramatically inhibits the growth of vemurafenib-resistant melanoma xenograft in vivo. Collectively, our findings have demonstrated that the combination of Skp2 inhibitor and USP14 inhibitor provides a new solution for the treatment of BRAF inhibitor resistance melanoma.

Combination of Paclitaxel and PXR Antagonist SPA70 Reverses Paclitaxel-Resistant Non-Small Cell Lung Cancer.

Paclitaxel (PTX) is one of the most efficient drugs for late-stage non-small cell lung cancer (NSCLC) patients. However, most patients gradually develop resistance to PTX with long-term treatments. The identification of new strategies to reverse PTX resistance in NSCLC is crucially important for the treatment. PTX is an agonist for the pregnane X receptor (PXR) which regulates PTX metabolism. Antagonizing PXR, therefore, may render the NSCLC more sensitive to the PTX treatment. In this study, we investigated the PXR antagonist SPA70 and its role in PTX treatment of NSCLC. In vitro, SPA70 and PTX synergistically inhibited cell growth, migration and invasion in both paclitaxel-sensitive and paclitaxel-resistant A549 and H460 lung cancer cells. Mechanistically, we found PTX and SPA70 cotreatment disassociated PXR from ABCB1 (MDR1, P-gp) promoter, thus inhibiting P-gp expression. Furthermore, the combination regimen synergistically enhanced the interaction between PXR and Tip60, which abrogated Tip60-mediated α-tubulin acetylation, leading to mitosis defect, S-phase arrest and necroptosis/apoptosis. Combination of PXT and SPA70 dramatically inhibited tumor growth in a paclitaxel-resistant A549/TR xenograft tumor model. Taken together, we showed that SPA70 reduced the paclitaxel resistance of NSCLC. The combination regimen of PTX and SPA70 could be potential novel candidates for the treatment of taxane-resistant lung cancer.

Relationship between maternal exposure to heavy metal titanium and offspring congenital heart defects in Lanzhou, China: A nested case-control study.

Background: Previous studies have found that exposure to heavy metals increased the incidence of congenital heart defects (CHDs). However, there is a paucity of information about the connection between exposure to titanium and CHDs. This study sought to examine the relationship between prenatal titanium exposure and the risk of CHDs in offspring. Methods: We looked back on a birth cohort study that was carried out in our hospital between 2010 and 2012. The associations between titanium exposure and the risk of CHDs were analyzed by using logistic regression analysis to investigate titanium concentrations in maternal whole blood and fetal umbilical cord blood. Results: A total of 97 case groups and 194 control groups were included for a nested case-control study. The [P50 (P25, P75)] of titanium were 371.91 (188.85, 659.15) µg/L and 370.43 (264.86, 459.76) µg/L in serum titanium levels in pregnant women and in umbilical cord serum titanium content in the CHDs group, respectively. There was a moderate positive correlation between the concentration of titanium in pregnant women's blood and that in umbilical cord blood. A higher concentrations of maternal blood titanium level was associated with a greater risk of CHDs (OR 2.706, 95% CI 1.547-4.734), the multiple CHDs (OR 2.382, 95% CI 1.219-4.655), atrial septal defects (OR 2.367, 95% CI 1.215-4.609), and patent ductus arteriosus (OR 2.412, 95% CI 1.336-4.357). Dramatically higher concentrations of umbilical cord blood levels had an increased risk of CHDs and different heart defects. Conclusion: Titanium can cross the placental barrier and the occurrence of CHDs may be related to titanium exposure.

Zeolite fly ash-enhanced coagulation treatment of oil recovery wastewater from polymer flooding.

Herein, an enhanced coagulation model is proposed in which zeolite is used as a crystal nucleus to promote flocs. The zeolite is prepared from fly ash by microwave-assisted hydrothermal synthesis. Scanning electron microscopy (SEM), X-ray diffraction (XRD), and specific surface area and pore size analysis (BET) characterization confirmed the successful synthesis of ZFA, and improved the surface properties. Thus, the adsorption capacity of ZFA as crystal nucleus was improved, which enabled it to achieve better results in the process of enhanced coagulation. Compared with those of conventional coagulation, the oil content and SS removal rate of ZFA-enhanced coagulation increased by 85% and 44%, respectively. Compared with that of CFA-enhanced coagulation, the oil removal efficiency increased by 4%, and the SS removal efficiency increased by 9%. The optimal conditions of ZFA-enhanced coagulation were as follows: ZFA dosage of 100 mg/L, pH value of 5-8, ZFA particle size range of 60-75 µm, temperature of 40-50 ℃, and precipitation time of 30 min.

Nuclear Receptor PXR Confers Irradiation Resistance by Promoting DNA Damage Response Through Stabilization of ATF3.

Low response rate to radiotherapy remains a problem for liver and colorectal cancer patients due to inappropriate DNA damage response in tumors. Here, we report that pregnane X receptor (PXR) contributes to irradiation (IR) resistance by promoting activating transcription factor 3 (ATF3)-mediated ataxia-telangiectasia-mutated protein (ATM) activation. PXR stabilized ATF3 protein by blocking its ubiquitination. PXR-ATF3 interaction is required for regulating ATF3, as one mutant of lysine (K) 42R of ATF3 lost binding with PXR and abolished PXR-reduced ubiquitination of ATF3. On the other hand, threonine (T) 432A of PXR lost binding with ATF3 and further compromised ATM activation. Moreover, the PXR-ATF3 interaction increases ATF3 stabilization through disrupting ATF3-murine double minute 2 (MDM2) interaction and negatively regulating MDM2 protein expression. PXR enhanced MDM2 auto-ubiquitination and shortened its half-life, therefore compromising the MDM2-mediated degradation of ATF3 protein. Structurally, both ATF3 and PXR bind to the RING domain of MDM2, and on the other hand, MDM2 binds with PXR on the DNA-binding domain (DBD), which contains zinc finger sequence. Zinc finger sequence is well known for nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) playing E3 ligase activity to degrade nuclear factor κB (NFκB)/p65. However, whether zinc-RING sequence grants E3 ligase activity to PXR remains elusive. Taken together, these results provide a novel mechanism that PXR contributes to IR resistance by promoting ATF3-mediated ATM activation through stabilization of ATF3. Our result suggests that targeting PXR may sensitize liver and colon cancer cells to IR therapy.

Redox-Based Strategy for Selectively Inducing Energy Crisis Inside Cancer Cells: An Example of Modifying Dietary Curcumin to Target Mitochondria.

Reprograming of energy metabolism is a major hallmark of cancer, but its effective intervention is still a challenging task due to metabolic heterogeneity and plasticity of cancer cells. Herein, we report a general redox-based strategy for meeting the challenge. The strategy was exemplified by a dietary curcumin analogue (MitoCur-1) that was designed to target mitochondria (MitoCur-1). By virtue of its electrophilic and mitochondrial-targeting properties, MitoCur-1 generated reactive oxygen species (ROS) more effectively and selectively in HepG2 cells than in L02 cells via the inhibition of mitochondrial antioxidative thioredoxin reductase 2 (TrxR2). The ROS generation preferentially mediated the energy crisis of HepG2 cells in a dual-inhibition fashion against both mitochondrial and glycolytic metabolisms, which could hit the metabolic plasticity of HepG2 cells. The ROS-dependent energy crisis also allowed its preferential killing of HepG2 cells (IC50 = 1.4 µM) over L02 cells (IC50 = 9.1 µM), via induction of cell-cycle arrest, apoptosis and autophagic death, and its high antitumor efficacy in vivo, in nude mice bearing HepG2 tumors (15 mg/kg). These results highlight that inhibiting mitochondrial TrxR2 to produce ROS by electrophiles is a promising redox-based strategy for the effective intervention of cancer cell energy metabolic reprograming.

The dynamics of cell death patterns and regeneration during acute liver injury in mice.

Acute liver injury is a serious clinical syndrome with multiple causes and unclear pathological process. Here, CCl4 - and D-galactosamine/lipopolysaccharide (D-gal/LPS)-induced acute liver injury was established to explore the cell death patterns and determine whether or not liver regeneration occurred. In CCl4 -induced hepatic injury, three phases, including the early, progressive, and recovery phase, were considered based on alterations of serum transaminases and liver morphology. Moreover, in this model, cytokines exhibited double-peak fluctuations; apoptosis and pyroptosis persisted throughout all phases; autophagy occurred in the early and the progressive phases; and sufficient and timely hepatocyte regeneration was observed only during the recovery phase. All of these phenomena contribute to mild liver injury and subsequent regeneration. Strikingly, only the early and progressive phases were observed in the D-gal/LPS model. Slight pyroptosis occurred in the early phase but diminished in the progressive phase, while apoptosis, reduced autophagy, and slight but subsequently diminished regeneration occurred only during the progressive phase, accompanied by a strong cytokine storm, resulting in severe liver injury with high mortality. Taken together, our work reveals variable modes and dynamics of cell death and regeneration, which lead to different consequences for mild and severe acute liver injury, providing a helpful reference for clinical therapy and prognosis.

Insights into the critical role of the PXR in preventing carcinogenesis and chemotherapeutic drug resistance.

Pregnane x receptor (PXR) as a nuclear receptor is well-established in drug metabolism, however, it has pleiotropic functions in regulating inflammatory responses, glucose metabolism, and protects normal cells against carcinogenesis. Most studies focus on its transcriptional regulation, however, PXR can regulate gene expression at the translational level. Emerging evidences have shown that PXR has a broad protein-protein interaction network, by which is implicated in the cross signaling pathways. Furthermore, the interactions between PXR and some critical proteins (e.g., p53, Tip60, p300/CBP-associated factor) in DNA damage pathway highlight its potential roles in this field. A thorough understanding of how PXR maintains genome stability and prevents carcinogenesis will help clinical diagnosis and finally benefit patients. Meanwhile, due to the regulation of CYP450 enzymes CYP3A4 and multidrug resistance protein 1 (MDR1), PXR contributes to chemotherapeutic drug resistance. It is worthy of note that the co-factor of PXR such as RXRα, also has contributions to this process, which makes the PXR-mediated drug resistance more complicated. Although single nucleotide polymorphisms (SNPs) vary between individuals, the amino acid substitution on exon of PXR finally affects PXR transcriptional activity. In this review, we have summarized the updated mechanisms that PXR protects the human body against carcinogenesis, and major contributions of PXR with its co-factors have made on multidrug resistance. Furthermore, we have also reviewed the current promising antagonist and their clinic applications in reversing chemoresistance. We believe our review will bring insight into PXR-targeted cancer therapy, enlighten the future study direction, and provide substantial evidence for the clinic in future.

Diagnostic accuracy of electronic surveillance tool for catheter-associated urinary tract infections in tertiary care hospitals: A meta-analysis.

BACKGROUND: Automated systems have been developed to reduce labor-intensive manual recordings during nosocomial infection surveillance. The diagnostic accuracies of these systems have differed in various settings. METHODS: We designed this meta-analysis to evaluate the diagnostic accuracy of an electronic surveillance tool for catheter-associated urinary tract infections (CAUTIs) in tertiary care hospitals. We systematically searched databases such as Medline, Scopus, Cochrane library and Embase (from inception until November 2019) for relevant studies. We assessed the quality of trials using the diagnostic accuracy studies-2 tool, and performed a meta-analysis to obtain a pooled sensitivity and specificity for electronic surveillance. We included 6 studies with 16,492 patients in the analysis. RESULTS: We found a pooled sensitivity of electronic diagnostic surveillance for CAUTIs of 97.5% (95% confidence interval [CI], 67.6-99.9%) and a pooled specificity of 92.6% (95% CI, 55.2-99.2%). The diagnostic odds ratio was 494 (95% CI, 89-2747). The positive likelihood ratio was 13.1 (95% CI, 1.63-105.8) and the negative likelihood ratio 0.02 (95% CI, 0.001-0.40). A bivariate box plot indicated the possibility of heterogeneity between the included studies. CONCLUSION: Our review suggests that electronic surveillance is useful for diagnosing CAUTIs among hospitalized patients in tertiary care hospitals due to its high sensitivity and specificity.

Emerging Roles of SKP2 in Cancer Drug Resistance.

More than half of all cancer patients receive chemotherapy, however, some of them easily acquire drug resistance. Resistance to chemotherapy has become a massive obstacle to achieve high rates of pathological complete response during cancer therapy. S-phase kinase-associated protein 2 (Skp2), as an E3 ligase, was found to be highly correlated with drug resistance and poor prognosis. In this review, we summarize the mechanisms that Skp2 confers to drug resistance, including the Akt-Skp2 feedback loop, Skp2-p27 pathway, cell cycle and mitosis regulation, EMT (epithelial-mesenchymal transition) property, enhanced DNA damage response and repair, etc. We also addressed novel molecules that either inhibit Skp2 expression or target Skp2-centered interactions, which might have vast potential for application in clinics and benefit cancer patients in the future.

Determining optimal gestational weight gain (GWG) in a northwest Chinese population: A CONSORT.

ABSTRACT: To determine optimal gestational weight gain (GWG) for the Chinese population.Live singleton deliveries at the largest maternal & childcare hospital in northwest China from 2010 to 2012 were analyzed retrospectively. Multivariable logistic regression analysis was conducted to determine the lowest aggregated risk of interested perinatal outcomes based on Chinese adult body mass index (BMI) categories.Eight thousand eight hundred seventy enrolled parturients were divided into 4 groups according to their prepregnancy BMI: underweight (21.31%, BMI < 18.5 kg/m2), normal weight (67.81%, 18.5 kg/m2 ≤ BMI < 24 kg/m2), overweight (8.99%, 24 kg/m2 ≤ BMI < 28 kg/m2 and obese (1.89%, BMI ≥ 28 kg/m2). The optimal GWG values for the above 4 groups were 16.7 kg (GWG range, 12.0-21.5), 14.5 kg (9.5-19.5), 11.5 kg (7.0-16.5), and 8.0 kg (5.0-13.0). The rates of inadequate, optimal and excessive GWG in present study were 6.14% (545), 62.34% (5529), and 31.52% (2796) respectively, which were significantly different from those of the 2009 Institute of Medicine recommendation (χ2 = 1416.05, Pinteraction < 0.0001).Wider optimal GWG ranges than those recommended by Institute of Medicine were found in our study, and our proposed criteria seems to be practical to the Chinese population.

What You Believe Can Affect How You Feel: Anger Among Caregivers of Elderly People With Dementia.

Background and Purpose: Anger has been recognized as a commonly experienced emotion among caregivers of elderly people with dementia. While several cognitive behavioral therapy (CBT)-based intervening methods have been developed, limited research has systematically examined the associations between dementia-related cognition and caregiving anger. Currently, we focused on three representative and well-studied cognitive constructs, person-centered attitude (PCA), dementia representation (DR), and empathy, exploring how they related to caregiving anger. Methods & Results: In total, 327 caregivers (239 female) participated in the study and finished online questionnaires. Multi-variable regression analyzes showed that PCA (ßPCA = -0.22**) and empathy (ßempathy = -0.18**) could negatively predict caregiving anger. However, all DR dimensions had no influence on caregiving anger except coherence (ßcoherence = -0.24**) in the current study. Conclusion: Generally, lower caregiving anger was associated with: (1) being more empathic; (2) having a person-centered attitude; and (3) having a comprehensive understanding of dementia. The results of this study provide detailed suggestions for the development of anger management programs for caregivers of people with dementia.

The Tubulin Inhibitor VERU-111 in Combination With Vemurafenib Provides an Effective Treatment of Vemurafenib-Resistant A375 Melanoma.

Melanoma is one of the deadliest skin cancers having a five-year survival rate around 15-20%. An overactivated MAPK/AKT pathway is well-established in BRAF mutant melanoma. Vemurafenib (Vem) was the first FDA-approved BRAF inhibitor and gained great clinical success in treating late-stage melanoma. However, most patients develop acquired resistance to Vem within 6-9 months. Therefore, developing a new treatment strategy to overcome Vem-resistance is highly significant. Our previous study reported that the combination of a tubulin inhibitor ABI-274 with Vem showed a significant synergistic effect to sensitize Vem-resistant melanoma both in vitro and in vivo. In the present study, we unveiled that VERU-111, an orally bioavailable inhibitor of α and ß tubulin that is under clinical development, is highly potent against Vem-resistant melanoma cells. The combination of Vem and VERU-111 resulted in a dramatically enhanced inhibitory effect on cancer cells in vitro and Vem-resistant melanoma tumor growth in vivo compared with single-agent treatment. Further molecular signaling analyses demonstrated that in addition to ERK/AKT pathway, Skp2 E3 ligase also plays a critical role in Vem-resistant mechanisms. Knockout of Skp2 diminished oncogene AKT expression and contributed to the synergistic inhibitory effect of Vem and VERU-111. Our results indicate a treatment combination of VERU-111 and Vem holds a great promise to overcome Vem-resistance for melanoma patients harboring BRAF (V600E) mutation.