Pan-immune-inflammation value as a prognostic biomarker for colon cancer and its variation by primary tumor location.

BACKGROUND: A growing body of research indicates significant differences between left-sided colon cancers (LCC) and right-sided colon cancers (RCC). Pan-immune-inflammation value (PIV) is a systemic immune response marker that can predict the prognosis of patients with colon cancer. However, the specific distinction between PIV of LCC and RCC remains unclear. AIM: To investigate the prognostic and clinical significance of PIV in LCC and RCC patients. METHODS: This multicenter retrospective cohort study included 1510 patients with colon cancer, comprising 801 with LCC and 709 with RCC. We used generalized lifting regression analysis to evaluate the relative impact of PIV on disease-free survival (DFS) in these patients. Kaplan-Meier analysis, as well as univariate and multivariate analyses, were used to examine the risk factors for DFS. The correlation between PIV and the clinical characteristics was statistically analyzed in these patients. RESULTS: A total of 1510 patients {872 female patients (58%); median age 63 years [interquartile ranges (IQR): 54-71]; patients with LCC 801 (53%); median follow-up 44.17 months (IQR 29.67-62.32)} were identified. PIV was significantly higher in patients with RCC [median (IQR): 214.34 (121.78-386.72) vs 175.87 (111.92-286.84), P < 0.001]. After propensity score matching, no difference in PIV was observed between patients with LCC and RCC [median (IQR): 182.42 (111.88-297.65) vs 189.45 (109.44-316.02); P = 0.987]. PIV thresholds for DFS were 227.84 in LCC and 145.99 in RCC. High PIV (> 227.84) was associated with worse DFS in LCC [PIV-high: Adjusted hazard ratio (aHR) = 2.39; 95% confidence interval: 1.70-3.38; P < 0.001] but not in RCC (PIV-high: aHR = 0.72; 95% confidence interval: 0.48-1.08; P = 0.114). CONCLUSION: These findings suggest that PIV may predict recurrence in patients with LCC but not RCC, underscoring the importance of tumor location when using PIV as a colon cancer biomarker.

ALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice.

Cardiac macrophage contributes to the development of cardiac fibrosis, but factors that regulate cardiac macrophages transition and activation during this process remains elusive. Here we show, by single-cell transcriptomics, lineage tracing and parabiosis, that cardiac macrophages from circulating monocytes preferentially commit to macrophage-to-myofibroblast transition (MMT) under angiotensin II (Ang II)-induced hypertension, with accompanying increased expression of the RNA N6-methyladenosine demethylases, ALKBH5. Meanwhile, macrophage-specific knockout of ALKBH5 inhibits Ang II-induced MMT, and subsequently ameliorates cardiac fibrosis and dysfunction. Mechanistically, RNA immunoprecipitation sequencing identifies interlukin-11 (IL-11) mRNA as a target for ALKBH5-mediated m6A demethylation, leading to increased IL-11 mRNA stability and protein levels. By contrast, overexpression of IL11 in circulating macrophages reverses the phenotype in ALKBH5-deficient mice and macrophage. Lastly, targeted delivery of ALKBH5 or IL-11 receptor α (IL11RA1) siRNA to monocytes/macrophages attenuates MMT and cardiac fibrosis under hypertensive stress. Our results thus suggest that the ALKBH5/IL-11/IL11RA1/MMT axis alters cardiac macrophage and contributes to hypertensive cardiac fibrosis and dysfunction in mice, and thereby identify potential targets for cardiac fibrosis therapy in patients.

Metastatic Pleomorphic Lobular Carcinoma of the Breast to the Urinary Bladder: A Report of 10 Cases and Assessment of TRPS1 in the Differential Diagnosis With Plasmacytoid Urothelial Carcinoma.

CONTEXT.­: Metastatic pleomorphic lobular carcinoma (MPLC) to the bladder is rare and has considerable histologic and immunohistochemical overlap with plasmacytoid urothelial carcinoma (PUC). OBJECTIVE.­: To distinguish MPLC from PUC morphologically and immunohistochemically, including a newer marker, TRPS1. DESIGN.­: Ten MPLCs to the bladder were reassessed and stained with estrogen, progesterone, and androgen receptors; GATA3; keratin 5/6; HMWK; GCDFP-15; and TRPS1. Sixteen PUCs constituted controls. RESULTS.­: We studied 4 transurethral resections of bladder tumors and 6 biopsies from 10 women (median age, 69 years) who had breast cancer on average 15 years prior. Microscopic patterns included single cells and cords of cells (n = 4), nests/sheets of dyscohesive cells (n = 2), or both (n = 4). All tumors had cells with voluminous eosinophilic cytoplasm and eccentric nuclei mimicking PUC, and 7 of 10 tumors had signet ring cells. MPLCs were positive for estrogen (8 of 10), progesterone (3 of 7), and androgen (4 of 10) receptors; GCDFP-15 (7 of 10); GATA3 (9 of 10); HMWK (7 of 8); and TRPS1 (7 of 10). No MPLCs stained for keratin 5/6 (n = 9). Of 16 PUCs, 2 showed faint and 2 demonstrated strong TRSP1 staining; 7 of 16 were negative for p63. CONCLUSIONS.­: MPLC to bladder often presents in patients with a remote history of breast cancer, exhibiting significant histologic and immunohistochemical overlap with PUC. Based on prior works and the current study, estrogen receptor (particularly SP-1), mammaglobin, and p63 help differentiate MPLC from PUC. Keratin 5/6 may aid in distinguishing a less frequent basal-type PUC because it is typically negative in MPLC. Some PUCs express TRPS1. Caution should be exercised because immunophenotypes of these tumors greatly overlap, and ramifications of misclassification are major.

The Characteristics of Macrophage Heterogeneity in Atherosclerotic Aortas.

Macrophage is the main effector cell during atherosclerosis. We applied single-cell RNA sequencing (scRNA) data to investigate the role of macrophage subsets in atherosclerosis. Monocyte and macrophage clusters were divided into 6 subclusters. Each subcluster's markers were calculated and validated by immunofluorescence. Elevated macrophage subclusters in the WD group were subject to enrichment pathway analysis and exhibited different phenotypes. Pseudotime analysis shows the subclusters originate from monocytes. We cultured bone marrow-derived macrophages with CSF-1 and ox-LDL to simulate an atherosclerotic-like environment and detected the transformation of subclusters. Macrophage-Vegfa and Macrophage-C1qb increased in the WD group. Macrophage-Vegfa acquires the characteristics of phagocytosis and immune response, while Macrophage-C1qb is not involved in lipid metabolism. The two subclusters are both enriched in cell movement and migration pathways. Experimental verification proved Monocyte-Ly6C evolved into Macrophage-Vegfa and Macrophage-C1qb during atherosclerosis progression.

Comparative analysis of the gut microbiota of wild adult rats from nine district areas in Hainan, China.

BACKGROUND: Wild rats have the potential to hold zoonotic infectious agents that can spread to humans and cause disease. AIM: To better understand the composition of gut bacterial communities in rats is essential for preventing and treating such diseases. As a tropical island located in the south of China, Hainan province has abundant rat species. Here, we examined the gut bacterial composition in wild adult rats from Hainan province. METHODS: Fresh fecal samples were collected from 162 wild adult rats, including three species (Rattus norvegicus, Leopoldamys edwardsi, and Rattus losea), from nine regions of Hainan province between 2017-2018. RESULTS: We analyzed the composition of gut microbiota using the 16S rRNA gene amplicon sequencing. We identified 4903 bacterial operational taxonomic units (30 phyla, 175 families, and 498 genera), which vary between samples of different rat species in various habitats at various times of the year. In general, Firmicutes were the most abundant phyla, followed by Bacteroidetes (15.55%), Proteobacteria (6.13%), and Actinobacteria (4.02%). The genus Lactobacillus (20.08%), unidentified_Clostridiales (5.16%), Romboutsia (4.33%), unidentified_Ruminococcaceae (3.83%), Bacteroides (3.66%), Helicobacter (2.40%) and Streptococcus (2.37%) were dominant. CONCLUSION: The composition and abundance of the gut microbial communities varied between rat species and locations. This work provides fundamental information to identify microbial communities useful for disease control in Hainan province.

Conversion immunotherapy for deficient mismatch repair locally unresectable colon cancer: A case report.

BACKGROUND: Owing to the special features of biologics, deficient mismatch repair (dMMR) in patients with colon cancer has achieved little treatment efficacy from chemoradiotherapy. Immunotherapy has shown promising results for the treatment of colon cancer. The high response rate observed suggests a great option for patients presenting with unresectable tumors, as it allows for better oncological resection. Here, we aimed to highlight the significant effects of immunotherapy on dMMR in colon cancer. CASE SUMMARY: A 54-year-old man diagnosed with locally unresectable dMMR colon cancer received preoperative immunotherapy (three cycles of pembrolizumab) and achieved a pathological complete response after surgery. CONCLUSION: Immunotherapy can be used as a conversion treatment for locally unresectable colon cancer with dMMR.

MG53 inhibits cellular proliferation and tumor progression in colorectal carcinoma.

Cancer is the second leading cause of mortality after cardiovascular diseases in the United States. Chemotherapy is widely used to treat cancers. Since the development of drug resistance is a major contributor towards the failure of chemotherapeutic regimens, efforts have been made to develop novel inhibitors that can combat drug resistance and sensitize cancer cells to chemotherapy. Here we investigated the anti-cancer effects of MG53, a TRIM-family protein known for its membrane repair functions. We found that rhMG53 reduced cellular proliferation of both parental and ABCB1 overexpressing colorectal carcinoma cells. Exogenous rhMG53 protein entered SW620 and SW620/AD300 cells without altering the expression of ABCB1 protein. In a mouse SW620/AD300 xenograft model, the combination of rhMG53 and doxorubicin treatment significantly inhibited tumor growth without any apparent weight loss or hematological toxicity in the animals. Our data show that MG53 has anti-proliferative function on colorectal carcinoma, regardless of their nature to drug-resistance. This is important as it supports the broader value for rhMG53 as a potential adjuvant therapeutic to treat cancers even when drug-resistance develops.

Spontaneous gallbladder perforation and colon fistula in hypertriglyceridemia-related severe acute pancreatitis: A case report.

BACKGROUND: Gallbladder perforation and gastrointestinal fistula are rare but serious complications of severe acute pancreatitis (SAP). However, neither spontaneous gallbladder perforation nor cholecysto-colonic fistula has been reported in acalculous acute pancreatitis patients. CASE SUMMARY: A 31-year-old male presenting with epigastric pain was diagnosed with hypertriglyceridemia-related SAP. He suffered from multiorgan failure and was able to leave the intensive care unit on day 20. Three percutaneous drainage tubes were placed for profound exudation in the peripancreatic region and left paracolic sulcus. He developed spontaneous gallbladder perforation with symptoms of fever and right upper quadrant pain 1 mo after SAP onset and was stabilized by percutaneous drainage. Peripancreatic infection appeared 1 mo later and was treated with antibiotics but without satisfactory results. Then multiple colon fistulas, including a cholecysto-colonic fistula and a descending colon fistula, emerged 3 mo after the onset of SAP. Nephroscopy-assisted peripancreatic debridement and ileostomy were carried out immediately. The fistulas achieved spontaneous closure 7 mo later, and the patient recovered after cholecystectomy and ileostomy reduction. We presume that the causes of gallbladder perforation are poor bile drainage due to external pressure, pancreatic enzyme erosion, and ischemia. The possible causes of colon fistulas are pancreatic enzymes or infected necrosis erosion, ischemia, and iatrogenic injury. According to our experience, localized gallbladder perforation can be stabilized by percutaneous drainage. Pancreatic debridement and proximal colostomy followed by cholecystectomy are feasible and valid treatment options for cholecysto-colonic fistulas. CONCLUSION: Gallbladder perforation and cholecysto-colonic fistula should be considered in acalculous SAP patients.

Appendiceal Neuroendocrine Tumor Is a Rare Cause of Ectopic Adrenocorticotropic Hormone Syndrome With Cyclic Hypercortisolism: A Case Report and Literature Review.

OBJECTIVE: Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a condition of hypercortisolism caused by non-pituitary tumors secreting ACTH. Appendiceal neuroendocrine tumor as a rare cause of ectopic ACTH syndrome was reported scarcely. We aimed to report a patient diagnosed with EAS caused by an appendiceal neuroendocrine tumor and summarized characteristics of these similar cases reported before. CASE REPORT AND LITERATURE REVIEW: We reported a case with Cushing's syndrome who was misdiagnosed as pituitary ACTH adenoma at first and accepted sella exploration. Serum and urinary cortisol decreased, and symptoms were relieved in the following 4 months after surgery but recurred 6 months after surgery. The abnormal rhythm of plasma cortisol and ACTH presented periodic secretion and seemingly rose significantly after food intake. EAS was diagnosed according to inferior petrosal sinus sampling (IPSS). Appendiceal mass was identified by 68Ga-DOTA-Tyr3-octreotate (DOTATATE)-PET-CT and removed. The pathological result was consistent with appendiceal neuroendocrine tumor with ACTH (+). The literature review demonstrated 7 cases diagnosed with EAS caused by appendiceal neuroendocrine tumor with similarities and differences. CONCLUSION: The diagnosis of an ectopic ACTH-producing tumor caused by the appendiceal neuroendocrine tumor can be a challenging procedure. Periodic ACTH and cortisol secretion may lead to missed diagnosis and misdiagnosis. IPSS is crucial in the diagnosis of EAS and 68Ga-DOTATATE-PET-CT plays an important role in the identification of lesions.

Lipid-Saporin Nanoparticles for the Intracellular Delivery of Cytotoxic Protein to Overcome ABC Transporter-Mediated Multidrug Resistance In Vitro and In Vivo.

Although the judicious use of anticancer drugs that target one or more receptor tyrosine kinases constitutes an effective strategy to attenuate tumor growth, drug resistance is commonly encountered in cancer patients. The ATP-binding cassette transporters are one of the major contributors to the development of multidrug resistance as their overexpression significantly decreases the intracellular concentration and thus, the efficacy of certain anticancer drugs. Therefore, the development of treatment strategies that would not be susceptible to efflux or excretion by specific ABC transporters could overcome resistance to treatment. Here, we investigated the anticancer efficacy of saporin, a ribosome-inactivating protein. Since saporin has poor permeability across the cell membrane, it was encapsulated in a lipid-based nanoparticle system (EC16-1) that effectively delivered the formulation (EC16-1/saporin) intracellularly and produced anti-cancer efficacy. EC16-1/saporin, at nanomolar concentrations, significantly inhibited the cellular proliferation of parental and ABCB1- and ABCG2-overexpressing cancer cells. EC16-1/saporin did not significantly alter the subcellular localization of ABCB1 and ABCG2. In addition, EC16-1/saporin induced apoptosis in parental and ABCB1- and ABCG2-overexpressing cancer cells. In a murine model system, EC16-1/saporin significantly inhibited the tumor growth in mice xenografted with parental and ABCB1- and ABCG2-overexpressing cancer cells. Our findings suggest that the EC16-1/saporin combination could potentially be a novel therapeutic treatment in patients with parental or ABCB1- and ABCG2-positive drug-resistant cancers.

Neoadjuvant chemoradiotherapy might provide survival benefit in patients with stage IIIb/IIIc locally advanced rectal cancer: A retrospective single-institution study with propensity score-matched comparative analysis.

BACKGROUND: Neoadjuvant chemoradiotherapy (NACRT) and total mesorectal excision (TME) are standard treatments of stage II/III locally advanced rectal cancer (LARC), currently. Here, we evaluated the oncological outcomes in LARC patients treated with NACRT compared to TME alone, and determined whether tumor regression grade (TRG) and pathologic response after NACRT was related to prognosis. METHODS: This is a retrospective comparison of 358 LARC patients treated with either TME alone (non-NACRT group, n = 173) or NACRT plus TME (NACRT group, n = 185) during 2003-2013. Perioperative and oncologic outcomes, like overall survival (OS), disease-free survival (DFS) and recurrence were compared using 1:1 propensity score matching analysis. RESULTS: A total of 133 patients were matched for the analysis. After a median follow-up of 45 months (8-97 months), the 5-year OS (NACRT vs non-NACRT: 75.42% vs 72.76%; P = 0.594) and 5-year DFS (NACRT vs non-NACRT: 74.25% vs 70.13%; P = 0.224) were comparable between NACRT and non-NACRT, whereas the 5-year DFS rate was higher in the NACRT group when only stage IIIb/IIIc patients were considered (NACRT vs. non-NACRT: 74.79% vs. 62.29%; P = 0.056). In the NACRT group of 185 patients, those with pCR/stage I (vs stage II/stage III disease) or TRG3/TRG4 disease (vs TRG0/TRG1/TRG2) had significantly better prognosis. CONCLUSION: NACRT might provide survival benefit in patients with stage IIIb/IIIc locally advanced rectal cancer.

Preclinical development of a novel BCR-ABL T315I inhibitor against chronic myeloid leukemia.

Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm primarily due to the presence of the BCR-ABL fusion gene that produces the constitutively active protein, BCR-ABL. Imatinib, a BCR-ABL-targeted drug, is a first-line drug for the treatment of CML. Resistance to imatinib occurs as a result of mutations in the BCR-ABL kinase domains. In this study, we evaluated S116836, a novel BCR-ABL inhibitor, for its anti-cancer efficacy in the wild-type (WT) and T315I mutant BCR-ABL. S116836 was efficacious in BaF3 cells with WT or T315I mutated BCR-ABL genotypes. S116836 inhibits the phosphorylation of BCR-ABL and its downstream signaling in BaF3/WT and BaF3/T315I cells. Mechanistically, S116836 arrests the cells in the G0/G1 phase of cell cycle, induces apoptosis, increases ROS production, and decreases GSH production in BaF3/WT and BaF3/T315I cells. Moreover, in mouse tumor xenografts, S116836 significantly inhibits the growth and volume of tumors expressing the WT or T315I mutant BCR-ABL without causing significant cardiotoxicity. Overall, our results indicate that S116836 significantly inhibits the imatinib-resistant T315I BCR-ABL mutation and could be a novel drug candidate for treating imatinib-resistant CML patients.

A single-center, prospective, randomized clinical trial to investigate the optimal removal time of the urinary catheter after laparoscopic anterior resection of the rectum: study protocol for a randomized controlled trial.

BACKGROUND: Urinary catheter placement is essential before laparoscopic anterior resection for rectal cancer. Whether early removal of the catheter increases the incidence of urinary retention and urinary tract infection (UTI) is not clear. This study aims to determine the optimal time for removal of the urinary catheter after laparoscopic anterior resection of the rectum. METHODS/DESIGN: A total of 220 participants meeting the inclusion criteria will be randomly assigned to an experimental group or a control group. The experimental group will have their urethral catheters removed on postoperative day 2 and the control group will have their urethral catheters removed on postoperative day 7. In both groups, catheter removal will be performed when the bladder is full. The incidence of urinary retention and UTI in the two groups will be compared to determine the optimal catheter removal time. DISCUSSION: This is a prospective, single-center, randomized controlled trial to determine whether early removal of the urinary catheter after laparoscopic anterior resection of the rectum will help to decrease the incidence of postoperative acute urinary retention and UTI. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03065855 . Registered on 23 February 2017.

Robotic versus conventional laparoscopic surgery for rectal cancer: systematic review and meta-analysis.

BACKGROUND: The purpose of this meta-analysis is to evaluate the evidence available on the safety as well as effectiveness of robotic resection as compared to conventional laparoscopic surgery for rectal cancer. MATERIAL AND METHODS: A comparison of laparoscopic and robotic surgical treatments for rectal cancer was collected. Eligible trials that analyzed probabilistic hazard ratios (HR) for endpoints of interest (including perioperative morbidity) and postoperative complications were included in our review. RESULTS: A total of six studies were included based on the present inclusion criteria. The pooled data showed that R-TME appeared to have association with remarkable reduction in the postoperative morbidity rate as compared to L-TME. Moreover, R-TME was also linked to lower conversion, decreased lymph node number, and longer operation time compared with L-TME. However, there was no difference in hospital stay, positive range of circumferential resection and blood loss between the two study groups. CONCLUSIONS: Robotic rectal cancer surgery provides favorable outcomes and is considered as a safe surgical technique in terms of postoperative oncological safety. Like laparoscopic TME surgery, robotic surgery may be a valid alternative and complementary approach with beneficial effects on minimally-invasive surgery.

Regorafenib antagonizes BCRP-mediated multidrug resistance in colon cancer.

Overexpression of breast cancer resistance protein (BCRP) has been shown to produce multidrug resistance (MDR) in colon cancer, leading to major obstacles for chemotherapy. In this study, we evaluated the effect of regorafenib, an oral multi-kinase inhibitor, in inhibiting BCRP-mediated MDR in silico, in vitro and in vivo. We found that regorafenib significantly sensitized MDR colon cancer cells to BCRP substrates by increasing their intracellular accumulation. There are no significant changes in the expression level or the subcellular distribution of BCRP in the cells exposed to regorafenib. Investigation of the mechanism revealed that regorafenib stimulated BCRP ATPase activity. Our induced-fit docking and molecular dynamics simulations suggested the existence of a strong and stable interaction between regorafenib and the transmembrane domain of human crystalized BCRP. In vivo tumor xenograft study revealed that the combination of regorafenib and topotecan exhibited synergistic effects on mitoxantrone-resistant S1-M1-80 xenograft tumors. In conclusion, our studies indicate that regorafenib would be beneficial in combating MDR in colon cancer.

Epidermal growth factor receptor (EGFR) inhibitor PD153035 reverses ABCG2-mediated multidrug resistance in non-small cell lung cancer: In vitro and in vivo.

One of the major mediators of multidrug resistance (MDR) in non-small cell lung cancer (NSCLC) is the overexpression of ATP-binding cassette subfamily G member 2 (ABCG2). In this study, we conducted in vitro and in vivo experiments to determine whether PD153035, an inhibitor of EGFR, could reverse ABCG2-mediated MDR in human NSCLC and transfected cells overexpressing ABCG2. The efficacy of SN-38, topotecan, and mitoxantrone (MX) were significantly increased by PD153035, PD153035 significantly reversed ABCG2-mediated MDR by attenuating the efflux activity of this transporter. In addition, PD153035 significantly down-regulated the expression of the ABCG2 transporter protein. Furthermore, a combination of PD153035 and topotecan, exhibited significant synergistic anticancer activity against mice xenografted with human H460/MX20 cells. These results, provided that they can be extrapolated to humans, suggest that the combination of topotecan and PD153035 could be a promising therapeutic strategy to attenuate the resistance to topotecan, as well as other anticancer drugs, mediated by the overexpression of ABCG2.

Regorafenib overcomes chemotherapeutic multidrug resistance mediated by ABCB1 transporter in colorectal cancer: In vitro and in vivo study.

Chemotherapeutic multidrug resistance (MDR) is a significant challenge to overcome in clinic practice. Several mechanisms contribute to MDR, one of which is the augmented drug efflux induced by the upregulation of ABCB1 in cancer cells. Regorafenib, a multikinase inhibitor targeting the RAS/RAF/MEK/ERK pathway, was approved by the FDA to treat metastatic colorectal cancer and gastrointestinal stromal tumors. We investigated whether and how regorafenib overcame MDR mediated by ABCB1. The results showed that regorafenib reversed the ABCB1-mediated MDR and increased the accumulation of [3H]-paclitaxel in ABCB1-overexpressing cells by suppressing efflux activity of ABCB1, but not altering expression level and localization of ABCB1. Regorafenib inhibited ATPase activity of ABCB1. In mice bearing resistant colorectal tumors, regorafenib raised the intratumoral concentration of paclitaxel and suppressed the growth of resistant colorectal tumors. But regorafenib did not induce cardiotoxicity/myelosuppression of paclitaxel in mice. Strategy to reposition one FDA-approved anticancer drug regorafenib to overcome the resistance of another FDA-approved, widely used chemotherapeutic paclitaxel, may be a promising direction for the field of adjuvant chemotherapy. This study provides clinical rationale for combination of conventional chemotherapy and targeted anticancer agents.

Selective reversal of BCRP-mediated MDR by VEGFR-2 inhibitor ZM323881.

The expression of breast cancer resistant protein (BCRP) in lung cancer is correlated with development of multidrug resistance (MDR) and therefore leads to lower response to chemotherapy. ZM323881, a previously developed selective VEGFR-2 inhibitor, was found to have inhibitory effects on BCRP-mediated MDR in this investigation. ZM323881 significantly decreased the cytotoxic doses of mitoxantrone and SN-38 in BCRP-overexpressing NCI-H460/MX20 cells. Mechanistic studies revealed that ZM323881 effected by inhibiting BCRP-mediated drug efflux, leading to intracellular accumulation of BCRP substrates. No significant alteration in the expression levels and localization pattern of BCRP was observed when BCRP-overexpressing cells were exposed to ZM323881. Stimulated bell-shaped ATPase activities were observed. Molecular docking suggested that ZM323881 binds to the modulator site of BCRP and the binding pose is stable validated by 100ns molecular dynamic simulation. Overall, our results indicated that ZM323881 reversed BCRP-related MDR by inhibiting its efflux function. These findings might be useful in developing combination chemotherapy for MDR cancer treatment.

Thiazole-valine peptidomimetic (TTT-28) antagonizes multidrug resistance in vitro and in vivo by selectively inhibiting the efflux activity of ABCB1.

Multidrug resistance (MDR) attenuates the chemotherapy efficacy and increases the probability of cancer recurrence. The accelerated drug efflux mediated by ATP-binding cassette (ABC) transporters is one of the major MDR mechanisms. This study investigated if TTT-28, a newly synthesized thiazole-valine peptidomimetic, could reverse ABCB1-mediated MDR in vitro and in vivo. TTT-28 reversed the ABCB1-mediated MDR and increased the accumulation of [3H]-paclitaxel in ABCB1 overexpressing cells by selectively blocking the efflux function of ABCB1, but not interfering with the expression level and localization of ABCB1. Animal study revealed that TTT-28 enhanced the intratumoral concentration of paclitaxel and promoted apoptosis, thereby potently inhibiting the growth of ABCB1 overexpressing tumors. But TTT-28 did not induce the toxicity (cardiotoxicity/myelosuppression) of paclitaxel in mice. In this study, we synthesized and evaluated a novel selective inhibitor of ABCB1 (TTT-28) with high efficacy and low toxicity. The identification and characterization of this new thiazole-valine peptidomimetic will facilitate design and synthesis of a new generation of ABCB1 inhibitors, leading to further research on multidrug resistance and combination chemotherapy. Furthermore, the strategy that co-administer MDR-ABCB1 inhibitor to overcome the resistance of one FDA approved, widely used chemotherapeutic paclitaxel, may be promising direction for the field of adjuvant chemotherapy.