Venlafaxine-Associated Rhabdomyolysis: A Literature Review.

PURPOSE: This systematic review aimed to investigate the clinical manifestations and characteristics of venlafaxine-associated rhabdomyolysis. METHODS: A systematic search was conducted in PubMed, Elsevier, Science Direct, Embase, Springer Link, Wiley Online Library, CNKI, and Wanfang databases from the date of database inception to January 2023. Previously reported cases of venlafaxine-associated rhabdomyolysis were identified, and relevant data from these cases were collected for descriptive statistical analysis. Cases that met the inclusion criteria were evaluated to determine the correlation between adverse reactions and venlafaxine. RESULTS: A total of 12 patients with venlafaxine-associated rhabdomyolysis were included. None of these patients had a history of muscle pain or discomfort. Of the 12 patients, 5 patients received venlafaxine at doses of ≤225 mg/d, whereas the remaining 7 patients received doses exceeding 225 mg/d. The main clinical symptoms included myalgia, muscle weakness, and renal injury. All 12 patients discontinued venlafaxine and received symptomatic care. CONCLUSIONS: Venlafaxine, used either as a monotherapy or in combination with other drugs, may be associated with rhabdomyolysis. Creatine kinase levels may normalize or significantly decrease after discontinuation of venlafaxine and symptomatic treatment.

Cost-effectiveness of pembrolizumab versus chemotherapy in patients with platinum-pretreated, recurrent or metastatic nasopharyngeal cancer.

BACKGROUND: Programmed cell death protein 1 (PD-1) monoclonal antibody, pembrolizumab, is a promising drug for platinum-pretreated, recurrent or metastatic nasopharyngeal cancer (NPC). We aimed to assess the cost-effectiveness of pembrolizumab compared with chemotherapy for Chinese patients in this NPC. METHODS: The cost-effectiveness of pembrolizumab versus chemotherapy was evaluated using a partitioned survival model with a 5-year boundary. Efficacy and toxicity data were derived from the KEYNOTE-122 trials. Economic indicators including life-years (LYs), quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), and lifetime cost were used. One-way analysis and probabilistic sensitivity analysis (PSA) were performed to explore the uncertainties. Additionally, various scenario analyses, including different pembrolizumab price calculations and discount rates were performed. RESULTS: Pembrolizumab or chemotherapy alone respectively yielded 2.82 QALYs (3.96 LYs) and 2.73 QALYs (3.93 LYs) with an ICER of $422,535 per QALYs ($1,232,547 per LYs). This model was primarily influenced by the price of pembrolizumab. Furthermore, PSA indicated that pembrolizumab had none probability of being cost-effective compared with chemotherapy at a willingness-to- pay (WTP) of $38223. Scenario analyses revealed that irrespective of any potential price reduction or adjustments in the discount rate, no discernible impact on the ultimate outcome was observed. CONCLUSION: Pembrolizumab was less cost-effective for patients with platinum-pretreated, recurrent or metastatic NPC compared with chemotherapy in China.

Cost-effectiveness of BTK inhibitors vs bendamustine and rituximab in chronic lymphocytic leukemia patients.

Background: We aimed to compare the cost-effectiveness of bruton tyrosine kinase inhibors (BTKis) versus bendamustine-rituximab (R-bendamustine) as a first-line treatment for Chinese patients with relapsed or refractory chronic lymphocytic leukemia. Methods: A partitioned survival model was constructed using TreeAge Pro 2022 software and transition probabilities were estimated from the reported survival probabilities using parametric survival modeling. One-way analysis and probabilistic sensitivity analysis were performed to explore the uncertainty of the modeling results. In addition, several scenario analyses were evaluated. Results: In comparison to R-bendamustine, zanubrutinib had an incremental cost-effectiveness ratio (ICER; life years) and ICER (quality-adjusted life years) of US$12,173.38 and $17,983.40, respectively. While ibrutinib had a higher ICER relative to R-bendamustine. Conclusion: Zanubrutinib was cost-effective for patients with relapsed or refractory chronic lymphocytic leukemia in China.

A colloidal gold test strip based on catalytic hairpin assembly for the clinical detection of influenza a virus nucleic acid.

Influenza A epidemics, which occur annually in varying degrees worldwide, is a global challenge to healthcare facilities owing to several limitations of the current detection methods. Therefore, the development of a rapid, convenient, and economical method for the early diagnosis of influenza A will aid clinical treatment and epidemic control. Currently, most of the commonly used clinical rapid tests utilize colloidal gold test strips that detect specific influenza virus antigens but are limited by low sensitivity. Therefore, this study combined catalytic hairpin assembly (CHA) with colloidal gold immunochromatographic assay (GICA) to develop a highly sensitive and visual CHA-GICA test strip. Clinical sample analysis revealed that the sensitivity of the assay was 81.8% and 74% under optimal (35 °C) and room temperature (25 °C) conditions, respectively. In conclusion, this study developed a rapid nucleic acid assay for detecting influenza A virus with high sensitivity and specificity, which can improve the clinical detection of influenza A.

Veratricplatin inhibits the progression of hypopharyngeal squamous cell carcinoma FaDu cells in vitro and in vivo.

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) ranks as the sixth most prevalent cancer. In recent years, the modification of platinum(II) into platinum(IV) derivative compounds, by introducing biologically active molecules, has been extensively employed to develop novel platinum-based prodrugs. We investigated the anti-proliferative activity against HNSCC of a new veratric acid (COX-2 inhibitor)-platinum(IV) complex. METHODS: In this study, a new veratric acid (COX-2 inhibitor)-platinum(IV) complex, termed veratricplatin, was synthesized. We evaluated the anti-tumor effect of in vitro and in vivo by western blotting, flow cytometry and DNA damage analysis. RESULTS: Veratricplatin displayed remarkable anti-proliferative activity against various cancer cell lines, including A549, FaDu, HeLa, and MCF-7. Furthermore, veratricplatin demonstrated significantly stronger cytotoxicity than either platinum(II) or veratric acid monotherapy or their combination. Importantly, the synthesized prodrug exhibited less toxicity toward normal cells (MRC-5), while dramatically enhanced DNA damage in FaDu cells inducing apoptosis. Moreover, veratricplatin markedly reduced the migration ability of FaDu cells compared to the control or monotherapy. In vivo, veratricplatin displayed potent anti-tumor activity with no apparent toxicity in BALB/c nude mice bearing FaDu tumors. In addition, tissue immunofluorescence analysis revealed that veratricplatin could substantially inhibit the formation of tumor blood vessels. CONCLUSION: Veratricplatin demonstrated remarkable drug efficacy, in terms of increased cytotoxicity in vitro and high efficiency with low toxicity in vivo.

The Development of HDAC and Tubulin Dual-Targeting Inhibitors for Cancer Therapy.

Histone deacetylases (HDACs) are a class of enzymes that are responsible for the removal of acetyl groups from the ε-N-acetyl lysine of histones, allowing histones to wrap DNA more tightly. HDACs play an essential role in many biological processes, such as gene regulation, transcription, cell proliferation, angiogenesis, migration, differentiation and metastasis, which make it an excellent target for anticancer drug discovery. The search for histone deacetylase inhibitors (HDACis) has been intensified, with numerous HDACis being discovered, and five of them have reached the market. However, currently available HDAC always suffers from several shortcomings, such as limited efficacy, drug resistance, and toxicity. Accordingly, dual-targeting HDACis have attracted much attention from academia to industry, and great advances have been achieved in this area. In this review, we summarize the progress on inhibitors with the capacity to concurrently inhibit tubulin polymerization and HDAC activity and their application in cancer treatment.

Dual-targeted and dual-sensitive self-assembled protein nanocarrier delivering hVEGI-192 for triple-negative breast cancer.

Breast cancer is a highly prevalent malignancy worldwide among women with an increasing incidence in recent years. Triple-negative breast cancer (TNBC), a specific type of breast cancer, occurs primarily in young women and exhibits large tumor size, high clinical stage, and extremely poor prognosis with a high rate of lymph node, liver, and lung metastases. TNBC is insensitive to endocrine therapy and trastuzumab treatment, and there is an urgent need for effective therapeutics and treatment guidelines. However, investigations into antiangiogenic agents for the treatment of TNBC are ongoing. In this study, we successfully engineered a self-assembled protein nanocarrier TfRBP9-hVEGI-192-ELP fusion protein (TVEFP) to deliver the therapeutic protein, human vascular endothelial growth inhibitor (hVEGI-192). This was found to be effective in inhibiting tumor angiogenesis in vivo. The protein nanocarrier effectively inhibited the progression of TNBC in vivo and showed the behavior of self-assembly, thermoresponsiveness, enzyme stimulation-responsiveness, tumor-targeting, biocompatibility, and biodegradability. Near-infrared imaging studies showed that fluorescent dye-stained TVEFP effectively aggregated at the tumor site. The TVEFP nanocarrier significantly expands the application of the therapeutic protein hVEGI-192 and improves the imaging and biotherapeutic effects in TNBC, chiefly based on anti-angiogenesis effects.

Addition of dNTPs can improve the detection sensitivity of catalytic hairpin assembly.

Ever since the catalytic hairpin assembly (CHA) circuit has been highlighted as a powerful nucleic acid detection tool, nucleic acid detection methods based on CHA have been widely studied. However, the detection sensitivity of CHA-based methods is insufficient. The relatively high background signals resulting from the spontaneous reaction between the two hairpin probes is one of the major reasons for limiting the sensitivity of CHA. In this study, we established that the addition of deoxynucleotide triphosphates (dNTPs) to the reaction system can significantly reduce the background leakage of CHA. The dNTPs-CHA, coupled with a fluorescence lateral flow assay strip, is used for the rapid and highly sensitive detection of miRNA. It is capable of reliably detecting miRNA in serum samples down to a limit of 100 aM, which is an improvement in the lower detection limit by nearly five orders of magnitude compared to that of the pure CHA.

A simple and programmable dual-mode aptasensor for the ultrasensitive detection of multidrug-resistant bacteria.

Accurately identifying multidrug-resistant (MDR) bacteria from clinical samples has long been a challenge. Herein, we report a simple and programmable dual-mode aptasensor called DAPT to reliably detect MDR bacteria. The DAPT method comprises two elements, namely the mode of dynamic light scattering (Mode-DLS) for ultrasensitive detection and the mode of fluorescence (Mode-Flu) for reliable quantification as a potent complement. Benefiting from the states of aptamer-modified gold nanoparticles (AptGNPs) sensitively changing from dispersion to aggregation, the proposed Mode-DLS achieved the rapid, specific, and ultrasensitive detection of methicillin-resistant Staphylococcus aureus (MRSA) at the limit of detection (LOD) of 4.63 CFU mL-1 in a proof-of-concept experiment. Simultaneously, the Mode-Flu ensured the accuracy of the detection, especially at a high concentration of bacteria. Moreover, the feasibility and universality of the DAPT platform was validated with four other superbugs by simply reprogramming the corresponding sequence. Overall, the proposed DAPT method based on a dual-mode aptasensor can provide a universal platform for the rapid and ultrasensitive detection of pathogenic bacteria due to its superior programmability.

Cost-effectiveness of rezvilutamide versus bicalutamide and androgen-deprivation therapy in patients with highvolume, metastatic, hormone-sensitive prostate cancer.

Background: Rezvilutamide, a novel androgen-receptor inhibitor with limited blood-brain barrier penetration, exhibits significant antitumour activity against highvolume, metastatic, hormone-sensitive prostate cancer (mHSPC). In this study, we aimed to compare the cost-effectiveness of rezvilutamide and bicalutamide as first-line treatments for untreated prostate cancer among Chinese patients, in order to evaluate the efficacy of rezvilutamide. Methods: In this study, we utilized partition survival model to assess the cost-effectiveness of rezvilutamide and bicalutamide treatments for highvolume mHSPC. The model was developed using TreeAge Pro 2022 software and relied on clinical data obtained from the CHART trial. Transition probabilities were estimated from the reported survival probabilities in trials using parametric survival modeling. From the perspective of the Chinese healthcare system, we calculated quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER), and lifetime cost. A lifetime horizon and an annual discount rate of 5% were employed. To address modeling uncertainties, we conducted one-way sensitivity analysis and probabilistic sensitivity analysis. Results: The cost of rezvilutamide versus bicalutamide were $62700 and $13200. Rezvilutamide had an ICER of $41900 per additional QALYs gained compared with bicalutamide. Research indicated that rezvilutamide achieved at least an 28.20% probability of cost-effectiveness at the threshold of $38223.34/QALY. One-way sensitivity analysis revealed that the results were sensitive to utility of PD. Scenario analysis showed that rezvilutamide was cost-effectiveness if its price was reduced by more than 10%. Conclusion: Based on the analysis at the current price, rezvilutamide was found to be less cost-effective for patients with highvolume mHSPC compared to bicalutamide in China.

Detection of Ureaplasma urealyticum by Catalytic Hairpin Assembly Combined with a Lateral Flow Immunoassay Strip.

Ureaplasma urealyticum is a common genital mycoplasma in men and women, which can cause reproductive tract infection and infertility, and is also related to adverse pregnancy outcomes and neonatal diseases. Pathogen culture and polymerase chain reaction (PCR) are the main methods for the diagnosis of U. urealyticum. However, pathogen culture takes too long, and PCR requires professional personnel and sophisticated instruments. Here, we report a simple, convenient, sensitive, and specific detection method, which combines catalytic hairpin assembly with a lateral flow immunoassay strip. Only a water bath and a fluorescence reader are needed to detect the results in 30 min. We can realize the point-of-care testing of U. urealyticum by this method. To verify this method, we selected 10 clinical samples for testing, and the test results were exactly the same as the clinical report.

Facile, Rapid, and Low-Cost Detection for Influenza Viruses and Respiratory Syncytial Virus Based on a Catalytic DNA Assembly Circuit.

Influenza viruses and respiratory syncytial virus (RSV) have contributed to severe respiratory infections, causing huge economic and healthcare burdens. To achieve rapid and precise detection of influenza viruses and RSV, we proposed a catalytic hairpin assembly (CHA) combined with the lateral flow immunoassay (CHA-LFIA) detection method. The presence of the target RNA triggers the initiation of CHA circuits. H1/H2 complexes, the amplified signal products, which were labeled with digoxin and biotin, were detected with a highly sensitive lateral flow immunoassay system. The sensitivity of the CHA-LFIA system to influenza A and B viruses and RSV reached up to 1, 1, and 5 pM, respectively. In addition, this method exhibited excellent capability for differentiating between target RNA and base-mismatched RNA. The results demonstrated that an enzyme-free, rapid, highly sensitive, and specific method had been developed to detect influenza A and B viruses and RSV.

Engineering a multi-target therapy nanoplatform against tumor growth and metastasis via a novel NSAID-Pt(IV) prodrug.

Tumor growth and metastasis are caused by many factors. The complexity means that a multi-target combination therapy strategy should be selected against tumor growth and metastasis. Here, cisplatin (CDDP) and bendazac (Ben) were designed as a novel NSAID-Pt(IV) nanoplatform, which is an effective weapon for combating tumor growth and metastasis.

High expression of CLEC10A in head and neck squamous cell carcinoma indicates favorable prognosis and high-level immune infiltration status.

Immunotherapy has emerged as a promising treatment modality for HNSCC. However, only a small proportion of HNSCC patients experience clinical benefits from immunotherapy and identifying molecular markers that can serve as effective prognostic signatures and predictive indicators for immunotherapy response in patients with HNSCC is critical. CLEC10A has attracted attention because of its important role in improving the antitumor activity of immune cells. However, to our knowledge, no study has evaluated the role of CLEC10A in HNSCC prognosis, progression, and immune microenvironment. In the present study, we comprehensively analyzed expression profiles of CLEC10A and its association with tumor progression, HPV status, and survival of patients. Moreover, we explored the association between CLEC10A expression relative to immune infiltration and the response to immunotherapy. We explored the association between the timing of the receipt of palliative care relative to cancer diagnosis and survival. Our results revealed that CLEC10A has decreased expression in HNSCC compared with normal tissues, and that low expression of CLEC10A was associated with an advanced clinical stage and poor prognosis. Furthermore, a higher level of CLEC10A expression correlated with immune infiltration presence and response to immunotherapy in HNSCC. Thus, we demonstrated that CLEC10A could be a potential prognostic marker in patients with HNSCC, and a potential target for immunotherapy.

Comprehensive analysis of matrix metalloproteinases and their inhibitors in head and neck squamous cell carcinoma.

Objective: This study aimed to explore the association of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) with cancer progression and prognosis in head and neck squamous cell carcinoma (HNSCC).Methods: Differentially expressed genes (DEGs) were identified by LIMMA package using R software. The correlation between the expression levels of MMPs and TIMPs in HNSCC cancer samples and adjacent normal tissue samples was performed using Pearson correlation analysis. The Kruskal-Wallis test (H-test) was used to determine the association between the expression level of MMPs/TIMPs and HNSCC clinical stage. The survival result was expressed as a KM curve, and the log-rank test was used for statistical analysis. Lasso regression and multivariate Cox regression analyses were used to examine whether the gene signature based on MMPs and TIMPs was an independent prognostic factor in patients with HNSCC.Results: Among the top 10 most up-regulated genes in HNSCC cancer tissues when compared with normal tissues, six genes belonged to the MMPs. Spearman correlation analysis revealed that only MMP11 and MMP23B were positively correlated with tumor stage. Survival analysis showed that patients with a high expression of MMP14, MMP20, TIMP1, and TIMP4 had a worse prognosis than low expression patients. Additionally, a novel five-gene (MMP3, MMP17, MMP19, MMP24, and TIMP1) signature was constructed and significantly associated with prognosis as an independent prognostic signature.Conclusions: Our data show that the accuracy of a single gene of MMP or TIMP as predictors of progression and prognosis of HNSCC is limited, although some studies have proposed that MMPs act as driving factors for cancer progression. The prediction performance of the five-gene signature prediction model was much better than that of the gene signatures based on every single gene in prognosis prediction.

Sensitive detection of hepatitis C virus using a catalytic hairpin assembly coupled with a lateral flow immunoassay test strip.

Currently, PCR is the gold standard for the detection of hepatitis C virus (HCV). However, the PCR technique is complicated and time-consuming, which prevents its application and, clinical point-of-care testing (POCT). Herein, we report a POCT method with simplicity, high sensitivity and specificity, which consists of a catalytic hairpin assembly (CHA) signal amplification system coupled with a lateral flow immunochromatographic (LFIA) test strip for the detection of HCV. Two ingeniously designed hairpin probes were hybridized to form the H1-H2 duplex in the presence of the target DNA. The catalytic hairpin assembly which was characterized of isothermal and enzyme-free, was accomplished within 40 min and the reaction was then applied to a LFIA test strip. Only the H1-H2 duplex labeled with both digoxin and biotin could be captured by the test strip, and the fluorescence value was determined. In addition, we evaluated the application potential for the detection of clinical samples. The reported method demonstrated high sensitivity with a detectable minimum concentration at 1 fM and showed a good linear range from 10 nM to 10pM, and high specificity for various mismatched sequences. The results demonstrated that clinically positive samples could be successfully detected. In conclusion, the reported method is simple, rapid, and free of large-scale equipment. POCT is expected to be useful for HCV detection in clinic.

Cost-effectiveness of fuzuloparib compared to routine surveillance, niraparib and olaparib for maintenance treatment of patients with germline BRCA1/2 mutation and platinum-sensitive recurrent ovarian carcinoma in China.

Background: Maintenance therapy with the poly (ADP-ribose) polymerase inhibitors (PARPis) for platinum-sensitive recurrent ovarian carcinoma (OC) have proven to be effective compared with placebo. We aimed to evaluate the cost-effectiveness (CE) of maintenance fuzuloparib compared to routine surveillance (RS), niraparib and olaparib for platinum-sensitive recurrent OC from the Chinese healthcare systems. Method: A partitioned survival model with three-state (progression-free, progressed, death) was constructed utilizing TreeAge Pro 2011 software to evaluate the economic value of fuzuloparib, niraparib and olaparib maintenance treatment for platinum-sensitive recurrent OC based on the clinical data derived from FZOCUS-2, ENGOT-OV16/NOVA and ENGOT-Ov21/SOLO2. Transition probabilities were estimated from the reported survival probabilities in those trials. Cost and health preference data were derived from the literature. The quality-adjusted life-years (QALYs) and lifetime costs were measured for this analysis. A 5 years horizon and 5%/year discount rates were used. One-way analysis, and probabilistic sensitivity analysis (PSA) were performed to explore the model uncertainties. Results: Total cost of fuzuloparib, niraparib and olaparib were $31628.10, $48183.48 and $54605.54, whereas they had an incremental cost-utility ratio of $31992.69, $32216.08 and $23359.26 per additional progression-free survival (PFS) QALYs gained compared with RS, relatively. Model showed that maintenance fuzuloparib achieved at least an 85.5% probability of CE at the threshold of $37654.50/QALY. One-way sensitivity analysis revealed that the results were sensitive to the PFS and the price of medicines. Conclusion: Fuzuloparib was less cost-effective for patients with germline BRCA1/2 mutation and platinum-sensitive recurrent OC compared to olaparib, but was superior to niraparib from the Chinese healthcare systems perspective.

CD13 Induces Autophagy to Promote Hepatocellular Carcinoma Cell Chemoresistance Through the P38/Hsp27/CREB/ATG7 Pathway.

The chemoresistance of hepatocellular carcinoma (HCC) is a serious problem that directly hinders the effect of chemotherapeutic agents. We previously reported that Aminopeptidase N (CD13) inhibition can enhance the cytotoxic efficacy of chemotherapy agents. In the present study, we use liver cancer cells to explore the molecular mechanism accounting for the relationship between CD13 and chemoresistance. We demonstrate that CD13 overexpression activates the P38/heat shock protein 27/cAMP response element-binding protein (CREB) signaling pathway to limit the efficacy of cytotoxic agents. Moreover, blockade of P38 or CREB sensitizes HCC cells to 5-fluorouracil. Then we reveal that CREB binds to the autophagy related 7 (ATG7) promoter to induce autophagy and promote HCC cell chemoresistance. CD13 inhibition also downregulates the expression of ATG7, autophagy, and tumor cell growth in vivo. Overall, the combination a CD13 inhibitor and chemotherapeutic agents may be a potential strategy for overcoming drug resistance in HCC. SIGNIFICANCE STATEMENT: Our study demonstrates that Aminopeptidase N (CD13) promotes hepatocellular carcinoma (HCC) cell chemoresistance via the P38/heat shock protein 27/cAMP response element-binding protein (CREB) pathway. CREB regulates autophagy related 7 transcription and expression to induce autophagy. Our results collectively suggest that CD13 may serve as a potential target for overcoming HCC resistance.

A new method to evaluate the enzyme-suppressing activity of a leucine aminopeptidase 3 inhibitor.

The expression of leucine aminopeptidase 3 (LAP3) is associated with the prognosis for and malignant transformation of many types of tumors. Therefore, a LAP3 inhibitor may represent a new strategy for cancer therapy. Evaluating the suppression of enzyme activity by an LAP3 inhibitor is essential. Right now, leucine aminopeptidases (LAPs) purified from the porcine kidneys are the only enzymes that can be used to evaluate the suppression of enzyme activity by an LAP3 inhibitor. This approach cannot accurately reflect the suppression of human LAP3 by an inhibitor. The current study developed a new method with which to evaluate the suppression of enzyme activity by an LAP3 inhibitor. Total protein from K562 cells seldom catalyzed the LAP3 substrate. A lentivirus was used to induce K562 cells to overexpress LAP3 (K562-LAP3). After puromycin screening, flow cytometry data indicated that 98.8% of cells expressed green fluorescent protein. The expression of LAP3 in K562-LAP3 cells was also assessed using Western blotting. K562-LAP3 cells were lysed with ultrasonication. Total protein was used as an enzyme source and L-leucine p-nitroaniline hydrochloride was used as a substrate to measure enzyme activity. Total protein from K562-LAP3 cells catalyzed the substrate more than that from K562 cells did. The LAP3 inhibitor ubenimex was used as a positive control to evaluate the suppression of LAP3 enzyme activity. Results indicated that ubenimex significantly inhibited the enzyme activity of LAP3. This approach provides a convenient and accurate way to evaluate the suppression of enzyme activity by an LAP3 inhibitor.

CD13 Inhibition Enhances Cytotoxic Effect of Chemotherapy Agents.

Multidrug resistance (MDR) of hepatocellular carcinoma is a serious problem. Although CD13 is a biomarker in human liver cancer stem cells, the relationship between CD13 and MDR remains uncertain. This study uses liver cancer cell model to understand the role of CD13 in enhancing the cytotoxic effect of chemotherapy agents. Cytotoxic agents can induce CD13 expression. CD13 inhibitor, bestatin, enhances the antitumor effect of cytotoxic agents. Meanwhile, CD13-targeting siRNA and neutralizing antibody can enhance the cytotoxic effect of 5-fluorouracil (5FU). CD13 overexpression increases cell survival upon cytotoxic agents treatment, while the knockdown of CD13 causes hypersensitivity of cells to cytotoxic agents treatment. Mechanistically, the inhibition of CD13 leads to the increase of cellular reactive oxygen species (ROS). BC-02 is a novel mutual prodrug (hybrid drug) of bestatin and 5FU. Notably, BC-02 can inhibit cellular activity in both parental and drug-resistant cells, accompanied with significantly increased ROS level. Moreover, the survival time of Kunming mice bearing H22 cells under BC-02 treatment is comparable to the capecitabine treatment at maximum dosage. These data implicate a therapeutic method to reverse MDR by targeting CD13, and indicate that BC-02 is a potent antitumor compound.