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Paclitaxel

"A cyclodecane isolated from the bark of the Pacific yew tree, TAXUS BREVIFOLIA. It stabilizes MICROTUBULES in their polymerized form leading to cell death." (MeSH 2013)

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Latest Research Publications

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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Petrella F, Coccè V, Masia C, et al.
Paclitaxel-releasing mesenchymal stromal cells inhibit in vitro proliferation of human mesothelioma cells.
Biomed Pharmacother. 2017; 87:755-758 [PubMed] Related Publications
INTRODUCTION: Malignant pleural mesothelioma (MPM) is a rare fatal asbestos-related malignancy originating in the mesothelial cells of the pleura. A platinum-based doublet containing a third-generation antifolate is the front-line standard of care whilst there are no approved second-line treatments for MPM which remains a disease setting to test the efficacy of new therapeutic agents.
METHODS: Bone marrow mesenchymal stromal cells (BM-MSCs) were loaded with pemetrexed (PMX) and paclitaxel (PTX) according to a standardized procedure. Drug release by both PMX- and PTX-primed BM-MSCs (BM-MSCs/PMX and BM-MSCs/PTX) was tested on the in vitro proliferation of a panel of tumor cell lines including NCI-H28 mesothelioma.
RESULTS: The in vitro anticancer activity of pure PTX was significantly higher than that of PMX against all the cell lines tested (14.7 times higher than that of PMX against NCI-H28). Whereas BM-MSCs did not take up and release PMX in amounts effective on mesothelioma, PTX-loaded BM-MSCs dramatically inhibited mesothelioma proliferation.
CONCLUSIONS: PTX-primed mesenchymal stromal cells successfully inhibit the in vitro proliferation of human mesothelioma cells. Further studies and in vivo testing are required to confirm our preliminary in vitro results as a potential new mesothelioma therapy based on cell drug delivery.

Li J, Yi W, Jiang P, et al.
Effects of ambroxol hydrochloride on concentrations of paclitaxel and carboplatin in lung cancer patients at different administration times.
Cell Mol Biol (Noisy-le-grand). 2016; 62(13):85-89 [PubMed] Related Publications
Our previous preliminary study revealed a synergistic effect of ambroxol hydrochloride with chemotherapeutic agents such as paclitaxel and carboplatin in lung cancer. However, the optimal conditions such as administration time and drug concentration of ambroxol hydrochloride to achieve the maximum synergistic effect remained unclear. Therefore, concentration changes of the chemotherapy drugs paclitaxel and carboplatin in the sputum were observed after ambroxol hydrochloride administration at different times in order to determine the most effective time frame of ambroxol hydrochloride administration. In this study, 470 cases of non-small cell lung cancer (NSCLC) were divided into different groups with ambroxol hydrochloride administered at different time points prior to chemotherapy, while another 171 cases received no ambroxol hydrochloride prior to chemotherapy. The results showed the concentrations of paclitaxel and carboplatin in sputum of patients treated with ambroxol hydrochloride were significantly higher than those of the control group, suggesting that ambroxol hydrochloride significantly increased the local concentrations of chemotherapeutic agents in lung tissues of NSCLC. Furthermore, the intravenous administration of ambroxol hydrochloride more than 48 hours before chemotherapy showed an optimized schedule and much greater efficacy in increasing drug concentrations than that of the control group. No statistical differences were found in the rates of grade 2 or above myelosuppression between the ambroxol intervention and control groups. Taken together, these results demonstrate that ambroxol hydrochloride administered intravenously more than 48 hours prior to chemotherapy optimally increased the concentrations of paclitaxel and carboplatin in lung tissue without significantly increasing hematologic toxicity.

Murakami T, Murata T, Kawaguchi K, et al.
Cervical Cancer Patient-Derived Orthotopic Xenograft (PDOX) Is Sensitive to Cisplatinum and Resistant to Nab-paclitaxel.
Anticancer Res. 2017; 37(1):61-65 [PubMed] Related Publications
BACKGROUND: Cervical cancer is a world-wide problem that requires transformative therapeutic strategies. We have previously developed patient-derived orthotopic xenograft (PDOX) nude-mouse models of this disease. In the present report, we demonstrate that the standard drug, cisplatinum (CDDP), is highly-effective while the new, highly-touted agent, nab-paclitaxel (NAB-PTX) is ineffective.
MATERIALS AND METHODS: Cervical PDOX tumors were grown on the cervix of nude mice for 4 weeks after surgical orthotopic implantation (SOI). Tumors were treated with CDDP or NAB-PTX.
RESULTS: H&E staining demonstrated that the PDOX tumor recapitulated the original patient tumor. CDDP was highly-effective. One tumor that was treated with CDDP completely regressed. CDDP-treated tumors were smaller (tumor volume ratio: 0.42±0.36) than the control group (tumor volume ratio: 3.47±1.66) (p<0.01). In contrast, NAB-PTX did not show significant efficacy on the cervical cancer PDOX model (tumor volume ratio: 2.85±1.45) (p=0.47). CDDP-treated tumor weight (50±50 mg) was significantly less than control (238±114 mg) (p<0.01). NAB-PTX-treated tumors were not reduced in weight (246±136 mg) compared to control (p=0.91). There were no significant differences in mouse body weight between groups. Histological evaluation demonstrated that CDDP-treated tumors were fibrotic with scattered squamous cell nests compared to control or NAB-PTX-treated tumors.
CONCLUSION: The results of the present study demonstrate the power of PDOX models of cervical cancer to distinguish efficacy of potential therapeutics for individual patients with this disease.

Liu J, Meng T, Yuan M, et al.
MicroRNA-200c delivered by solid lipid nanoparticles enhances the effect of paclitaxel on breast cancer stem cell.
Int J Nanomedicine. 2016; 11:6713-6725 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: One of the major obstacles in the treatment of breast cancer is breast cancer stem cells (BCSC) which are resistant to standard chemotherapeutic drugs. It has been proven that microRNA-200c (miR-200c) can restore sensitivity to microtubule-targeting chemotherapeutic drugs by reducing the expression of class III β-tubulin. In this study, combination therapy with miR-200c and paclitaxel (PTX) mediated by lipid nanoparticles was investigated as an alternative strategy against BCSC.
MATERIALS AND METHODS: A cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane was strategically selected to formulate solid lipid nanoparticles (SLN) for miR-200c delivery. Nanostructured lipid carriers (NLC) with 20 wt% oleic acid were prepared for PTX delivery. Mammospheres, which gained the characteristics of BCSC, were used as a cell model to evaluate the efficiency of combination therapy.
RESULTS: The cationic SLN could condense anionic miRNA to form SLN/miRNA complexes via charge interactions and could protect miRNA from degradation by ribonuclease. SLN/miR-200c complexes achieved 11.6-fold expression of miR-200c after incubation for 24 hours, compared with that of Lipofectamine™ 2000/miR-200c complexes (*P<0.05). Intracellular drug release assay proved that miRNA can be released from SLN/miRNA complexes efficiently in 12 hours after cellular uptake. After BCSC were transfected with SLN/miR-200c, the expression of class III β-tubulin was effectively downregulated and the cellular cytotoxicity of PTX-loaded NLC (NLC/PTX) against BCSC was enhanced significantly (**P<0.01).
CONCLUSION: The results indicated that the cationic SLN could serve as a promising carrier for miRNA delivery. In addition, the combination therapy of miR-200c and PTX revealed a novel therapeutic strategy for the treatment of BCSC.

Wang F, Du X, Li X, et al.
Effects of sequential paclitaxel-carboplatin followed by gemcitabine-based chemotherapy compared with paclitaxel-carboplatin therapy administered to patients with advanced epithelial ovarian cancer: A retrospective, STROBE-compliant study.
Medicine (Baltimore). 2016; 95(51):e5696 [PubMed] Free Access to Full Article Related Publications
We aimed to compare the efficacy of paclitaxel and carboplatin followed by gemcitabine-based combination chemotherapy with paclitaxel-carboplatin for treating advanced epithelial ovarian cancer in this retrospective, STROBE-compliant study. Patients' tolerance to treatment was also assessed.We retrospectively analyzed the records of 178 women who underwent initial optimal debulking surgery between January 2003 and December 2011 to treat FIGO stage IIIc epithelial ovarian cancer. Patients in arm 1 (n = 88) received 4 cycles of paclitaxel and carboplatin followed by 2 to 4 cycles of gemcitabine-based combination chemotherapy. Patients in arm 2 (n = 90) received 6 to 8 cycles of paclitaxel and carboplatin. The granulocyte-colony stimulating factor was administered prophylactically to all patients.The median follow-up for both arms was 62 months. Medianprogression-free survival (PFS) between arms 1 and 2 (28 and 19 months [P = 0.003]) as well as 5-year OS (34.1% and 18.9% [P = 0.021]) differed significantly. The neurotoxicity rate was significantly higher in arm 2 than in arm 1 (45.2% vs 27.1%, P = 0.026). There was no significant difference between study arms in hematological toxicity.The sequential regimen significantly improved PFS and 5-year OS with tolerable toxicity compared with the single regimen, and offers an alternative for treating patients with advanced epithelial ovarian cancer.

Li Y, Guo M, Lin Z, et al.
Polyethylenimine-functionalized silver nanoparticle-based co-delivery of paclitaxel to induce HepG2 cell apoptosis.
Int J Nanomedicine. 2016; 11:6693-6702 [PubMed] Free Access to Full Article Related Publications
Hepatocarcinoma is the third leading cause of cancer-related deaths around the world. Recently, a novel emerging nanosystem as anticancer therapeutic agents with intrinsic therapeutic properties has been widely used in various medical applications. In this study, surface decoration of functionalized silver nanoparticles (AgNPs) by polyethylenimine (PEI) and paclitaxel (PTX) was synthesized. The purpose of this study was to evaluate the effect of Ag@ PEI@PTX on cytotoxic and anticancer mechanism on HepG2 cells. The transmission electron microscope image and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that Ag@PEI@PTX had satisfactory size distribution and high stability and selectivity between cancer and normal cells. Ag@PEI@PTX-induced HepG2 cell apoptosis was confirmed by accumulation of the sub-G1 cells population, translocation of phosphatidylserine, depletion of mitochondrial membrane potential, DNA fragmentation, caspase-3 activation, and poly(ADP-ribose) polymerase cleavage. Furthermore, Ag@PEI@PTX enhanced cytotoxic effects on HepG2 cells and triggered intracellular reactive oxygen species; the signaling pathways of AKT, p53, and MAPK were activated to advance cell apoptosis. In conclusion, the results reveal that Ag@ PEI@PTX may provide useful information on Ag@PEI@PTX-induced HepG2 cell apoptosis and as appropriate candidate for chemotherapy of cancer.

Cui Y, She K, Tian D, et al.
miR-146a Inhibits Proliferation and Enhances Chemosensitivity in Epithelial Ovarian Cancer via Reduction of SOD2.
Oncol Res. 2016; 23(6):275-282 [PubMed] Related Publications
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, accounting for 90% of all ovarian cancer. Dysregulation of miRNAs is associated with several types of EOC. In the current research, we aimed to study the role of abnormal expression of miR-146a in the development of EOC and to elucidate the possible molecular mechanisms. Compared with control samples, mRNA expression of miR-146a was significantly decreased in EOC tissues and cell lines. Overexpression of miR-146a prohibited cell proliferation, enhanced apoptosis, and increased sensitivity to chemotherapy drugs in EOC cells. In contrast, downregulation of miR-146a promoted cell proliferation, suppressed apoptosis, and decreased sensitivity to chemotherapy drugs in EOC cells. Overexpression of miR-146a increased the reactive oxygen species (ROS) level and decreased SOD2 mRNA and protein expression. Downregulation of miR-146a increased SOD2 mRNA and protein expression. Overexpression of SOD2 significantly inhibited miR-146a mimics-induced suppression of cell proliferation and the increase of apoptosis and chemosensitivity. In conclusion, we identify miR-146a as a potential tumor suppressor in patients with EOC. miR-146a downregulates the expression of SOD2 and enhances ROS generation, leading to increased apoptosis, inhibition of proliferation, and enhanced sensitivity to chemotherapy. The data demonstrate that the miR-146a/SOD2/ROS pathway may serve as a novel therapeutic target and prognostic marker in patients with EOC.

Fukuchi M, Mochiki E, Ishiguro T, et al.
Efficacy of Nab-Paclitaxel as Second-line Chemotherapy for Unresectable or Recurrent Gastric Cancer.
Anticancer Res. 2016; 36(12):6699-6703 [PubMed] Related Publications
AIM: To evaluate the efficacy and safety of nanoparticle albumin-bound-paclitaxel (nab-PTX) as second-line chemotherapy (CT) for patients with unresectable or recurrent gastric cancer (GC).
PATIENTS AND METHODS: The clinicopathological and survival data of 37 patients with unresectable or recurrent GC who underwent nab-PTX monotherapy as second-line CT, were retrospectively analyzed.
RESULTS: The median number of cycles and relative dose intensity administered per patient were 5 and 90%, respectively. Their overall response rate was 24.3% and the disease control rate was 59.5%. Median progression-free survival (PFS) and overall survival were 4.8 months and 10.4 months, respectively. Thirteen patients had grade 3 or 4 toxicities and were managed. In multivariate Cox regression analysis, cycles of chemotherapy ≥5 (odds ratio, 0.20; 95% confidence interval, 0.08-0.50; p<0.01) was the only significant independent predictor of longer PFS.
CONCLUSION: Nab-PTX may effectively prevent disease progression as second-line CT by increasing treatment cycles and managing adverse effects.

Qi N, Li F, Li X, et al.
Combination use of paclitaxel and avastin enhances treatment effect for the NSCLC patients with malignant pleural effusion.
Medicine (Baltimore). 2016; 95(47):e5392 [PubMed] Free Access to Full Article Related Publications
The current study is conducted to investigate efficacy of the chemotherapy drug paclitaxel in combination with Avastin (Roche Diagnostics GmbH., Mannheim, Germany) (antiangiogenic agent) in treatment of malignant pleural effusions (MPEs).Twenty-four patients with non-small cell lung cancer were randomly assigned for 2 treatment approaches. Ten patients received paclitaxel (175 mg/m) alone, and 14 patients took a combination therapy of paclitaxel and Avastin (5 mg/kg). Efficacy of the treatment approaches in the patients was validated with the change in the MPE volume. Pharmacokinetic (PK) profile and urinary excretion rate of paclitaxel were analyzed with serum vascular endothelial growth factor (VEGF) level, and adverse events were examined as well.The combination therapy reduced the MPE level with a successful rate of 29% and a survival rate of 25% over the single paclitaxel treatment in the study cohort (both P < 0.05). PKs for the combined treatment displayed a rapid distribution of the anticancer drug paclitaxel with an obvious increase in its elimination half-life in the pleural fluid (both P < 0.01). Mean residence time of paclitaxel increased in the presence of Avastin (P < 0.01). Serum VEGF levels significantly reduced in the Avastin-treated patients as compared to the paclitaxel-treated ones (P < 0.01). The urinary excretion rate was similar in the study cohort. Incidence of adverse events for the 2 treatment approaches was similar in the patients.Intervention of Avastin enhances potency of paclitaxel in treatment of MPEs with the increased survival rate of the patients through inhibiting VEGF production and prolonging time of ongoing interaction between the chemotherapy drug and the tumor tissues.

Akyol Z, Çoker-Gürkan A, Arisan ED, et al.
DENSpm overcame Bcl-2 mediated resistance against Paclitaxel treatment in MCF-7 breast cancer cells via activating polyamine catabolic machinery.
Biomed Pharmacother. 2016; 84:2029-2041 [PubMed] Related Publications
PURPOSE: The Bcl-2 mediated resistance is one of the most critical obstacle in cancer therapy. Conventional chemotherapeutics such as Paclitaxel, a commonly used in the treatment of metastatic breast cancer, is not sufficient to overcome Bcl-2 mediated drug resistance mechanism. Thus, combinational drug regimes are favored by researchers to overcome resistance phenotype against drugs. N1,N11-diethylnorspermine (DENSpm), a polyamine analogue, which is a promising drug candidate induced-cell cycle arrest and apoptosis in various cancer cells such as prostate, melanoma, colon and breast cancer cells via activated polyamine catabolism and reactive oxygen generation. Recent studies indicated the potential therapeutic role of DENSpm in phase I and II trials in breast cancer cases. Although the molecular targets of Paclitaxel in apoptotic cell death mechanism is well documented, the therapeutic effect of DENSpm and Paclitaxel in breast cancer cells has not been investigated yet. In this study, our aim was to determine the time dependent effect of DENSpm and Paclitaxel on apoptotic cell death via determination of polyamine metabolism related targets in wt and Bcl-2 overexpressing MCF-7 breast cancer cells.
RESULTS: In our experimental study, Paclitaxel decreased cell viability in dose-dependent manner within 24h. Co-treatment of Paclitaxel (30nM) with DENSpm (20μM) further increased the cytoxicity of Paclitaxel (30nM) compared to alone Paclitaxel (30nM) treatment in MCF-7 Bcl-2+ breast cancer cells. In addition, we determined that resistance against Paclitaxel-induced apoptotic cell death in Bcl-2 overexpressed MCF-7 cells was overcome due to activation of polyamine catabolic pathway, which caused depletion of polyamines.
CONCLUSIONS: DENSpm combinational treatment might increase the effect of low cytotoxic paclitaxel in drug-resistant breast cancer cases.

Choi HS, Cho SG, Kim MK, et al.
SH003 enhances paclitaxel chemosensitivity in MCF-7/PAX breast cancer cells through inhibition of MDR1 activity.
Mol Cell Biochem. 2017; 426(1-2):1-8 [PubMed] Related Publications
Paclitaxel is an anti-cancer drug for treating cancer, but paclitaxel resistance is reported in cancer cells. Multidrug resistance (MDR) is related with the epithelial-to-mesenchymal transition (EMT) mechanism, which plays a key role in cancer metastasis. Moreover, EMT mechanism is connected to tamoxifen resistance in breast cancer cells. Consequently, oncologists are interested in finding new MDR1 inhibitors originating from herbal medicines to have less side-effect. Here, we investigated an inhibition effect of SH003 on MDR1 activity in paclitaxel-resistant MCF-7/PAX breast cancer cells. Our results showed that paclitaxel did not inhibit a proliferation in paclitaxel-resistant MCF-7 breast cancer cells. Paclitaxel-resistant MCF-7 cells showed an increase of MDR1 activity, which was confirmed by measuring an amount of accumulated rhodamine 123 in the cells. Also, qRT-PCR and Western blot assays confirmed that paclitaxel-resistant MCF-7 cells exhibited high MDR1 expression level. Furthermore, paclitaxel-resistant MCF-7 cells showed mesenchymal morphology with alterations of EMT markers, and acquired tamoxifen resistance with a decrease of ERα expression. We also found that a combinatorial treatment of SH003 and paclitaxel in paclitaxel-resistant MCF-7 cells caused apoptosis in synergistic manner, which was due to SH003 inhibition of MDR1 expression. Therefore, SH003 could be a potential agent for overcoming MDR in drug-resistant cancer cells.

Takeda K, Matsushita H, Kubozono M, et al.
Definitive Chemoradiotherapy for Advanced Pulmonary Sarcomatoid Carcinoma.
Intern Med. 2016; 55(22):3325-3330 [PubMed] Free Access to Full Article Related Publications
Pulmonary sarcomatoid carcinoma is a rare subtype of non-small cell lung cancer with a poor prognosis. We herein report on a case of pulmonary sarcomatoid carcinoma that was treated successfully by concurrent chemoradiotherapy. A 65-year-old man was diagnosed to have pulmonary pleomorphic carcinoma (clinical T4N2M0 stage IIIB). He received concurrent chemoradiotherapy (60 Gy of radiotherapy in 30 fractionations and two courses of chemotherapy with carboplatin and paclitaxel). After chemoradiotherapy, a significant reduction of the tumor size was observed. Two courses of adjuvant chemotherapy were performed. He is currently alive at 15 months after the first treatment without any recurrence or metastasis.

Rades D, Seidl D, Wollenberg B, et al.
Radiochemotherapy with Paclitaxel for Recurrent Previously Irradiated Squamous Cell Carcinoma of the Head and Neck.
Anticancer Res. 2016; 36(10):5463-5468 [PubMed] Related Publications
BACKGROUND/AIM: Locoregional recurrences of squamous cell carcinoma of the head and neck (SCCHN) are difficult to treat. If radiotherapy was included in the primary treatment, another curative course of radiotherapy incurs substantial risk of complications. Results of re-irradiation can be improved by concurrent chemotherapy.
PATIENTS AND METHODS: Radiotherapy with low doses per fraction twice daily and paclitaxel were applied in four patients with recurrent SCCHN. Radiotherapy was administered with doses of 30-36 Gy and doses per fraction of 1.5 Gy twice daily. Concurrent chemotherapy consisted of 20-25 mg/m(2) paclitaxel twice per week. Overall 1-year locoregional control following re-irradiation was 25%. One-year locoregional control rates were 75% inside the re-irradiated region and 50% outside the re-irradiated region. Distant metastases did not occur. One-year overall survival following re-irradiation was 75%. Toxicity did not exceed grade 2.
CONCLUSION: Re-irradiation plus concurrent paclitaxel appeared well-tolerated and resulted in promising outcomes.

Dong K, Yan Y, Wang P, et al.
Biodegradable mixed MPEG-SS-2SA/TPGS micelles for triggered intracellular release of paclitaxel and reversing multidrug resistance.
Int J Nanomedicine. 2016; 11:5109-5123 [PubMed] Free Access to Full Article Related Publications
In this study, a type of multifunctional mixed micelles were prepared by a novel biodegradable amphiphilic polymer (MPEG-SS-2SA) and a multidrug resistance (MDR) reversal agent (d-α-tocopheryl polyethylene glycol succinate, TPGS). The mixed micelles could achieve rapid intracellular drug release and reversal of MDR. First, the amphiphilic polymer, MPEG-SS-2SA, was synthesized through disulfide bonds between poly (ethylene glycol) monomethyl ether (MPEG) and stearic acid (SA). The structure of the obtained polymer was similar to poly (ethylene glycol)-phosphatidylethanolamine (PEG-PE). Then the mixed micelles, MPEG-SS-2SA/TPGS, were prepared by MPEG-SS-2SA and TPGS through the thin film hydration method and loaded paclitaxel (PTX) as the model drug. The in vitro release study revealed that the mixed micelles could rapidly release PTX within 24 h under a reductive environment because of the breaking of disulfide bonds. In cell experiments, the mixed micelles significantly inhibited the activity of mitochondrial respiratory complex II, also reduced the mitochondrial membrane potential, and the content of adenosine triphosphate, thus effectively inhibiting the efflux of PTX from cells. Moreover, in the confocal laser scanning microscopy, cellular uptake and 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assays, the MPEG-SS-2SA/TPGS micelles achieved faster release and more uptake of PTX in Michigan Cancer Foundation-7/PTX cells and showed better antitumor effects as compared with the insensitive control. In conclusion, the biodegradable mixed micelles, MPEG-SS-2SA/TPGS, could be potential vehicles for delivering hydrophobic chemotherapeutic drugs in MDR cancer therapy.

Liu Y, Gao S, Chen X, et al.
Overexpression of miR-203 sensitizes paclitaxel (Taxol)-resistant colorectal cancer cells through targeting the salt-inducible kinase 2 (SIK2).
Tumour Biol. 2016; 37(9):12231-12239 [PubMed] Related Publications
MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression through the endogenous RNA interference machinery. Treatments with combination of chemotherapy with surgery are essential for advanced-stage colorectal cancer. However, the development of chemoresistance is a major obstacle for clinical application of anticancer drugs. In this study, we report a miR-203-SIK2 axis that involves in the regulation of Taxol sensitivity in colon cancer cells. MiR-203 is downregulated in human colon tumor specimens and cell lines compared with their normal counterparts. We report miR-203 is correlated with Taxol sensitivity: overexpression of miR-203 sensitizes colon cancer cells and the Taxol-resistant cells display downregulated miR-203 compared with Taxol-sensitive cells. We identify SIK2 as a direct target of miR-203 in colorectal cancer cells. Overexpression of miR-203 complementary pairs to the 3' untranslated region (UTR) of SIK2, leading to the sensitization of Taxol resistant cells. In addition, miR-203 and the salt-inducible kinase 2 (SIK2) are reverse expressed in human colorectal tumors. Finally, we demonstrate recovery of SIK2 by overexpression of SIK2-desensitized Taxol-resistant cells, supporting the miR-203-mediated sensitization to Taxol, is through the inhibition of SIK2. In general, our study will provide mechanisms of the microRNA-based anti-tumor therapy to develop anti-chemoresistance drugs.

Cai G, Ma X, Chen B, et al.
Galectin-3 induces ovarian cancer cell survival and chemoresistance via TLR4 signaling activation.
Tumour Biol. 2016; 37(9):11883-11891 [PubMed] Related Publications
Paclitaxel resistance becomes common in patients with aggressive ovarian cancer and results in recurrence after conventional therapy. Galectin-3 is a multifunctional lectin associated with cell migration, cell proliferation, cell adhesion, and cell-cell interaction in tumor cells. Whether circulating galectin-3 is involved in paclitaxel resistance in ovarian cancer remains unknown. The current study investigated the effect of galectin-3 on toll-like receptor 4 (TLR4) signaling and thus paclitaxel resistance. With blood and cancer tissue samples obtained from 102 patients, we identified associations between serum galectin-3 level or TLR4 expression and paclitaxel resistance phenotype. In vitro, treatment with exogenous galectin-3 restored cell survival and migration of SKOV-3 and ES-2 cells was decreased by galectin-3 silencing and paclitaxel treatment. Furthermore, exogenous galectin-3 boosted expression of TLR4, MyD88, and p-p65, as well as interleukin (IL)-6, IL-8, and vascular endothelial growth factor (VEGF) release induced by paclitaxel. Moreover, galectin-3 inhibited the interaction between TLR4 and caveolin-1 (Cav-1) in SKOV-3 and ES-2 cells. In addition, overexpression of Cav-1 dampened the expression of MyD88 and p-p65 stimulated by galectin-3 and enhanced apoptosis in SKOV-3 cells under paclitaxel exposure. In summary, our study elucidated that exogenous galectin-3 might induce paclitaxel resistance through TLR4 signaling activation by inhibiting TLR4-Cav-1 interaction, revealing a novel insight into paclitaxel resistance induction.

Yu D, Li W, Zhang Y, Zhang B
Anti-tumor efficiency of paclitaxel and DNA when co-delivered by pH responsive ligand modified nanocarriers for breast cancer treatment.
Biomed Pharmacother. 2016; 83:1428-1435 [PubMed] Related Publications
CONTEXT: Combination of chemotherapy and nucleic acid therapy generally take advantage of drugs anti-tumor activity together with DNA capacity to transfect cancer cells, showing great promise in cancer treatment. However, effective co-delivery of drugs and DNA in a single carrier for cancer treatment remains a challenge.
OBJECTIVE: This study aimed to design a tumor targeted, pH sensitive nanocarriers for the co-delivery of gene and drug.
MATERIALS AND METHODS: Hyaluronic acid - acid sensitive linker - 1,2-distearoyl phosphatideylethanolamine copolymers (HA-as-DSPE) were synthesized. HA-as-DSPE modified, paclitaxel and pDNA loaded solid lipid nanoparticles (HA-PTX/pDNA SLN) was prepared. The physicochemical properties like morphology, size, and zeta potential as well as release properties were evaluated. The ability and therapeutic effects of the novel system for the co-delivery of PTX and pDNA were demonstrated in vitro and in vivo.
RESULTS: In vitro experiments and in vivo animal studies both confirmed that the HA-PTX/pDNA SLN system could promote the inhibition of tumor, at the same time deliver and transfect gene into the cancer cells.
DISCUSSION AND CONCLUSION: Highest efficiency achieved by HA-PTX/pDNA SLN might result from the HA ligands that targeted the receptors on the cancer cells, the enhanced cellular uptake by the SLN formulations and also the pH sensitive bound of the carriers let the drug release more in the tumor cells. It could be concluded that HA-PTX/pDNA SLN could be used as a promising delivery system for drug and gene combination therapy.

Mohammadi A, Mansoori B, Aghapour M, et al.
The Urtica dioica extract enhances sensitivity of paclitaxel drug to MDA-MB-468 breast cancer cells.
Biomed Pharmacother. 2016; 83:835-842 [PubMed] Related Publications
INTRODUCTION: Due to the chemo resistant nature of cancer cells and adverse effects of current therapies, researchers are looking for the most efficient therapeutic approach which has the lowest side effects and the highest toxicity on cancer cells. The aim of the present study was to investigate the synergic effect of Urtica dioica extract in combination with paclitaxel on cell death and invasion of human breast cancer MDA-MB-468 cell line.
MATERIALS AND METHODS: To determine the cytotoxic effects of Urtica dioica extract with paclitaxel, MTT assay was performed. The scratch test was exploited to assess the effects of Urtica dioica, Paclitaxel alone and combination on migration of cancer cells. The expression levels of snail-1, ZEB1, ZEB2, twist, Cdc2, cyclin B1 and Wee1 genes were quantified using qRT-PCR and western blot performed for snail-1expression. The effects of plant extract, Paclitaxel alone and combination on different phases of cell cycle was analyzed using flow cytometry.
RESULTS: Results of MTT assay showed that Urtica dioica significantly destroyed cancer cells. Interestingly, Concurrent use of Urtica dioica extract with paclitaxel resulted in decreased IC50 dose of paclitaxel. Moreover, findings of scratch assay exhibited the inhibitory effects of Urtica dioica, Paclitaxel alone and combination on migration of MDA-MB-468 cell line. Our findings also demonstrated that the extract substantially decreased the Snail-1 and related gene expression. Ultimately, Cell cycle arrest occurred at G2/M phase post-treatment by deregulating Cdc2 and wee1.
CONCLUSIONS: Our results demonstrated that the dichloromethane extract of Urtica dioica inhibit cell growth and migration. Also, Urtica dioica extract substantially increased sensitivity of breast cancer cells to paclitaxel. Therefore, it can be used as a potential candidate for treatment of breast cancer with paclitaxel.

Bo L, Cui H, Fang Z, et al.
Inactivation of transforming growth factor-β-activated kinase 1 promotes taxol efficacy in ovarian cancer cells.
Biomed Pharmacother. 2016; 84:917-924 [PubMed] Related Publications
Resistance to taxol represents a major obstacle for long-term remission in ovarian cancer. Transforming Growth Factor-β-Activated Kinase 1 (TAK1) is a critical component in immune response pathway. However, the role of TAK1 in the development of chemoresistance in ovarian cancer remains unknown. Here, we showed that in vitro, taxol-resistant cells expressed higher TAK1, and the ratio of p-TAK1/TAK1 positively associated with taxol resistance in ovarian cancer cells. Inactivation of TAK1 by inhibitor 5Z-7-oxozeaenol or gene knockdown sensitized taxol cytotoxicity in vitro, promoting cell apoptosis and mitosis arrest. Moreover, resistant cells were much more sensitive to the combined TAK1 inhibitor and taxol treatment than their parental counterparts. Using xenograft mouse model, we found that 5Z-7-oxozeaenol significantly enhanced taxol efficacy in vivo. Thus, targeting TAK1 pathway is a promising strategy to enhance taxol response in ovarian cancer treatment.

Yu B, Tian X, Zhang L, Feng R
Hematopoietic PBX-Interaction Protein Promotes Breast Cancer Sensitivity to Paclitaxel Through a Microtubule-Dependent Mechanism.
DNA Cell Biol. 2016; 35(11):740-745 [PubMed] Related Publications
AIMS: Recently, microtubule-binding proteins (MBPs) have been implicated in modulation of paclitaxel sensitivity in many cancers, highlighting their potential as biomarkers predictive of treatment outcomes and as therapeutic targets that can be pharmacologically manipulated. This study is aimed to determine the impact of the MBP hematopoietic PBX-interaction protein (HPIP) on breast cancer cell sensitivity to paclitaxel.
RESULTS: In this study, we show that breast cancer cells (MCF-7 and MDA-MB-231) overexpressing HPIP were more sensitive to paclitaxel treatment as evaluated by MTT assay, exhibiting a significant reduction in IC50 of paclitaxel compared with the control. In transwell assay, breast cancer cells overexpressing HPIP, but not the cells transfected with empty vector, showed significant migration inhibition in response to paclitaxel. Furthermore, in vitro assays show that combined HPIP and paclitaxel enabled a more rapid and more complete microtubule assembly than paclitaxel alone, and accordingly HPIP plus paclitaxel-stabilized microtubule displayed slower dissociation dynamics upon dilution and cooling. Notably, overexpression of HPIP decreased the cellular level of HDAC6, leading to increased acetylation of tubulin as shown by Western blot and immunofluorescence imaging analysis.
CONCLUSIONS: Collectively, HPIP sensitized breast cancer cells to paclitaxel through a microtubule-dependent mechanism. Our finding hints at a clinical value of HPIP in breast cancer patient selection for paclitaxel-based regimens in the context of precision medicine.

Chang Q, Geng R, Wang S, et al.
DOPA-based paclitaxel-loaded liposomes with modifications of transferrin and alendronate for bone and myeloma targeting.
Drug Deliv. 2016; 23(9):3629-3638 [PubMed] Related Publications
Treatment for multiple myeloma (MM) with a combined strategy of bone and tumor targeting remains a crucial technical challenge due to the incorporation of various functional components into one single system. Here, we developed dioleoyl phosphatidic acid (DOPA)-based paclitaxel (PTX)-loaded liposomes with modifications of alendronate and transferrin (Ald-/Tf-modified PTX-L), which were capable of bone affinity mediated by phosphate groups in DOPA and alendronate, and tumor targeting offered by transferrin. Ald-/Tf-modified PTX-L had clear and well-defined spherical shape with an intermediated size of 118.8 ± 4.8 nm, a highly negative surface charge of -46.9 ± 6.8 mV and a drug entrapment efficiency (DEE) of approximately 80%. When the pH was changed from pH 7.4 to pH 6.5, the accumulative release of PTX from Ald-/Tf-modified PTX-L significantly increased from 26.7 ± 3.7% to 41.7 ± 4.9%. Importantly, liposomes based on DOPA displayed an obviously stronger affinity with hydroxyapatite (HAp) than 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-based liposomes. Compared to PTX-L, Ald-/Tf-modified PTX-L exhibited obvious improvement of cytotoxicity (IC50 = 1.25 ± 0.09 μg/mL), significant enhancement on PTX intracellular accumulation (16.58 ± 0.62 μg/mg) and notable promotion to apoptosis induction (45.21 ± 3.10%) toward myeloma (MM1s) cells. In this study of antitumor efficacy, Ald-/Tf-modified PTX-L with bone-specific targeting showed a significant effect on extending the median survival time (48 days) and terminal survival time (> 58 days) against the MM1S-injected nude mice among all formulations. The results suggested that Ald-/Tf-modified PTX-L had potential as an efficient anticancer drug delivery system for MM therapy.

Dermitzakis EV, Kimiskidis VK, Lazaridis G, et al.
The impact of paclitaxel and carboplatin chemotherapy on the autonomous nervous system of patients with ovarian cancer.
BMC Neurol. 2016; 16(1):190 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Paclitaxel-based regimens are frequently associated with the development of peripheral neuropathy. The autonomous nervous system (ANS) effects, however, of this chemotherapeutic agent remain unexplored.
METHODS: We investigated a group of 31 female patients with ovarian cancer receiving treatment with paclitaxel and carboplatin, as well as a group of 16 healthy age- and gender-matched healthy volunteers. All study participants completed a questionnaire and were assessed neurophysiologically at three time points (baseline, 3-4 months and 6-8 months following the onset of chemotherapy). The evaluation of the ANS included assessment of the adrenergic cardiovascular function (orthostatic hypotension-OH), parasympathetic heart innervation (30/15 ratio) and sympathetic skin response (SSR).
RESULTS: At the 3-4 months ANS assessment, 19.2 % of the patients had systolic OH and the same percentage had diastolic OH, but at the 6-8 months evaluation no patient had systolic OH and only 13.8 % had diastolic OH. The values of the 30/15 ratio were significantly reduced at both time points, whereas the SSR was not affected.
CONCLUSIONS: Combined paclitaxel and carboplatin chemotherapy is associated with significant effects on the parasympathetic heart innervation and occasionally with effects on the adrenergic cardiovascular reaction. The SSR remained unaffected. Physicians should be alert to the possibility of these treatment-emergent side effects, so as to monitor ANS parameters and introduce treatment modifications accordingly. Our findings however, should be validated in larger cohorts.

Schettini F, Giuliano M, De Placido S, Arpino G
Nab-paclitaxel for the treatment of triple-negative breast cancer: Rationale, clinical data and future perspectives.
Cancer Treat Rev. 2016; 50:129-141 [PubMed] Related Publications
Triple-negative breast cancer (TNBC) accounts for ∼10-20% of breast cancers and is associated with relatively poor prognosis, earlier disease recurrence and higher number of visceral metastases. Despite an increasing understanding of the molecular heterogeneity of TNBC, clinical trials of targeted agents have thus far been disappointing; chemotherapy, in particular with anthracycline and taxanes, remains the backbone medical management for both early and metastatic TNBC. Nab-paclitaxel is a solvent-free, albumin-bound, nanoparticle formulation of paclitaxel and represents a novel formulation of an established, effective chemotherapeutic agent. Nab-paclitaxel has been specifically designed to overcome the limitations of conventional taxane formulations, including the barriers to effective drug delivery of highly lipophilic agents. It has shown significant efficacy and better tolerability than conventional taxanes in metastatic breast cancer and is approved for use in this setting. Increasing evidence suggests that nab-paclitaxel is effective in patients with more aggressive tumours, as seen in TNBC. Indeed, results of Phase II/III studies indicate that nab-paclitaxel may be effective as neoadjuvant treatment of TNBC. This article reviews the rationale and evidence supporting a role for nab-paclitaxel in the treatment of TNBC, including ongoing studies such as ADAPT-TN and tnAcity. In addition, the article reviews ongoing research into targeted therapies and immuno-oncology for the treatment of TNBC, and explores the potential role, current evidence and ongoing studies of nab-paclitaxel as the chemotherapy partner in combination with immunotherapy, where the unique properties of this taxane, including the lack of requirement for steroid pre-medication, may present an advantage.

Mo Q, Zhang Y, Jin X, et al.
Geldanamycin, an inhibitor of Hsp90, increases paclitaxel-mediated toxicity in ovarian cancer cells through sustained activation of the p38/H2AX axis.
Tumour Biol. 2016; 37(11):14745-14755 [PubMed] Related Publications
Paclitaxel is a mitotic inhibitor used in ovarian cancer chemotherapy. Unfortunately, due to the rapid genetic and epigenetic changes in adaptation to stress induced by anticancer drugs, cancer cells are often able to become resistant to single or multiple anticancer agents. However, it remains largely unknown how paclitaxel resistance happens. In this study, we generated a cell line of acquired resistance to paclitaxel therapy, A2780T, which is cross-resistant to other antimitotic drugs, such as PLK1 inhibitor or AURKA inhibitor. Immunoblotting revealed significant alterations in cell-cycle-related and apoptotic-related proteins involved in key signaling pathways. In particular, phosphorylation of p38, which activates H2AX, was significantly decreased in A2780T cells compared to the parental A2780 cells. Geldanamycin (GA), an inhibitor of Hsp90, sustained activation of the p38/H2AX axis, and A2780T cells were shown to be more sensitive to GA compared to A2780 cells. Furthermore, treatment of A2780 and A2780T cells with GA significantly enhanced sensitivity to paclitaxel. Meanwhile, GA cooperated with paclitaxel to suppress tumor growth in a mouse ovarian cancer xenograft model. In conclusion, GA may sensitize a subset of ovarian cancer to paclitaxel, particularly those tumors in which resistance is driven by inactivation of p38/H2AX axis.

Ye J, Xia X, Dong W, et al.
Cellular uptake mechanism and comparative evaluation of antineoplastic effects of paclitaxel-cholesterol lipid emulsion on triple-negative and non-triple-negative breast cancer cell lines.
Int J Nanomedicine. 2016; 11:4125-40 [PubMed] Free Access to Full Article Related Publications
There is no effective clinical therapy for triple-negative breast cancers (TNBCs), which have high low-density lipoprotein (LDL) requirements and express relatively high levels of LDL receptors (LDLRs) on their membranes. In our previous study, a novel lipid emulsion based on a paclitaxel-cholesterol complex (PTX-CH Emul) was developed, which exhibited improved safety and efficacy for the treatment of TNBC. To date, however, the cellular uptake mechanism and intracellular trafficking of PTX-CH Emul have not been investigated. In order to offer powerful proof for the therapeutic effects of PTX-CH Emul, we systematically studied the cellular uptake mechanism and intracellular trafficking of PTX-CH Emul and made a comparative evaluation of antineoplastic effects on TNBC (MDA-MB-231) and non-TNBC (MCF7) cell lines through in vitro and in vivo experiments. The in vitro antineoplastic effects and in vivo tumor-targeting efficiency of PTX-CH Emul were significantly more enhanced in MDA-MB-231-based models than those in MCF7-based models, which was associated with the more abundant expression profile of LDLR in MDA-MB-231 cells. The results of the cellular uptake mechanism indicated that PTX-CH Emul was internalized into breast cancer cells through the LDLR-mediated internalization pathway via clathrin-coated pits, localized in lysosomes, and then released into the cytoplasm, which was consistent with the internalization pathway and intracellular trafficking of native LDL. The findings of this paper further confirm the therapeutic potential of PTX-CH Emul in clinical applications involving TNBC therapy.

van der Woude SO, van Laarhoven HW
Acute hypertension during ramucirumab infusion in two patients with advanced oesophagogastric cancer.
BMJ Case Rep. 2016; 2016 [PubMed] Related Publications
Ramucirumab, a monoclonal antibody targeting the vascular endothelial growth factor (VEGF) pathway, in combination with paclitaxel is becoming part of standard second-line systemic therapy for advanced oesophagogastric cancer, based on the results of the REGARD and RAINBOW trials. Common well-known side effects of VEGF pathway inhibitors are hypertension and infusion-related reactions. Here, we describe hypertension as the predominant feature of an infusion-related reaction in 2 patients with metastasised oesophagogastric carcinoma treated with ramucirumab and paclitaxel as second-line treatment and propose possible explanations of this side effect previously undescribed for ramucirumab.

Chu T, Jiang L, Ying W, Han B
M30/M65 ratio predicts the outcome of paclitaxel chemotherapy for NSCLC.
Clin Transl Oncol. 2017; 19(3):326-331 [PubMed] Related Publications
PURPOSE: Paclitaxel is an effective treatment for some of the non-small-cell lung cancer (NSCLC) patients. However, prediction of the outcome of paclitaxel treatment at the early stage of the chemotherapy is difficult. M30 and M65 are circulating fragments of cytokeratin 18 released during apoptosis or necrosis, respectively, and have been used as markers to evaluate chemotherapy in some cancers. Here, we aimed to examine M30 and M65 values for predicting the therapeutic outcome of paclitaxel treatment of NSCLC.
METHODS: The serum levels of M30 and M65 before and after paclitaxel treatment in advance-stage NSCLC patients were analyzed, and compared to those in healthy controls. The importance of the M30 and M65 levels to the outcome of chemotherapy was analyzed.
RESULT: We found that the serum M30 and M65 levels were higher in patients with NSCLC (n = 44) than in control healthy subjects (n = 56) (p < 0.001). Two days after paclitaxel treatment, the serum levels of both M30 and M65 significantly increased in NSCLC patients (p < 0.001). Neither marker alone significantly correlated with overall patient survival, but the ratio of M30 vs M65 appeared to be an important prognostic factor for the overall survival of the patients (p < 0.01).
CONCLUSION: Our results suggest that the serum M30/M65 ratio may be a prognostic factor for the outcome of paclitaxel treatment in NSCLC.

Shen Y, Zhang XY, Chen X, et al.
Octreotide reverses the resistance of A2780/Pacliaxel ovarian cancer cell line to paclitaxel chemotherapy in vitro.
J Cancer Res Ther. 2016 Apr-Jun; 12(2):657-62 [PubMed] Related Publications
OBJECTIVE: To study the anti-tumor effects of octreotide on A2780/Taxol ovarian cancer cells in vitro, and further explore its potential molecular mechanism.
MATERIALS AND METHODS: Immunocytochemistry was performed to determine the expression of SSTR2 on A2780/Taxol cells. Octreotide at different concentrations (0, 1.25, 2.5, 5.0, 10.0, and 20.0 nmol/ml) were administrated to A2780/Taxol cells in vitro. CCK-8 assay was used to measure the effects on cell proliferation, and the cytometry of octreotide determined the cell apoptosis. The expressions of SSTR2 MDR1, and vascular endothelial growth factor (VEGF) messenger ribonucleic acid (mRNA) were investigated by quantitative reverse transcription polymerase chain reaction (RT-qPCR) assay and the expressions of the above protein were investigated after A2780/Taxol was treated with octreotide for 48 hours by western blot in vitro.
RESULTS: Positive expression of SSTR2 was observed on the membrane of A2780/Taxol cells. The proliferation of A2780/Taxol cells was gradually inhibited with increasing octreotide concentration in a concentration-dependent and time-dependent manner. Meanwhile, flow cytometry data demonstrated the octreotide-induced cell apoptosis. The results of SSTR2 mRNA suggested that there was no significant difference between each concentration group of octreotide (P > 0.05). Compared with the control group, both the MDR1 and VEGF mRNA decreased in a dose-dependent manner following 48 hours of treatment of octreotide (P < 0.05). The results of western blot showed that octreotide decreased the expressions of SSTR2, MDR1, and VEGF protein in a dose-dependent manner (P < 0.05).
CONCLUSIONS: Octreotide significantly inhibits ovarian cancer's proliferation and promotes its apoptosis via the cell surface expression of SSTR2. It could be used as a new targeted drug for treatment of ovarian cancer.

Tianqin G, Chunlei C, Jingjing W
Synergistic Anti-glioma Effects in Vitro and in Vivo of Enediyne Antibiotic Neocarzinostatin and Paclitaxel via Enhanced Growth Delay and Apoptosis-Induction.
Biol Pharm Bull. 2016; 39(10):1623-1630 [PubMed] Related Publications
Neocarzinostatin (NCS) is a member of enediyne antibiotics with high anticancer potential. Our study was performed to explore the synergistic anti-glioma effects of NCS and paclitaxel (PTX) in vitro and in vivo. By 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the cytotoxicities of the drugs to human glioma cells U87MG and rat glioma cells C6 were evaluated. The results showed that the combinations of NCS and PTX can synergistically inhibit glioma cells survival. Cell apoptosis was detected by flow cytometry, and the results showed that the combinations of NCS and PTX synergistically enhanced apoptosis ratio of glioma cells. Western blot revealed that the cell signaling pathways of proliferation and apoptosis were synergistically regulated, in which Akt was synergistically inactivated, p53 was up-regulated with down-regulation of bcl-2. Meanwhile, with the subcutaneous model of U87MG cells and intracerebral implantation model of C6 cells, the combination strategy could synergistically delay the glioma growth and significantly prolong the survival of rats bearing orthotopic glioma. This study demonstrates that the combination of NCS and PTX can potentiate the effect on survival and apoptosis of glioma cells via suppression of Akt, bcl-2, and activations of p53; Meanwhile, the in vivo studies also confirmed that the combination of NCS and PTX synergistically inhibit the gliom growth. Our data about the combinational effects of NCS with PTX may provide an alternative strategy for glioma therapy.

Pan Q, Xue M, Xiao SS, et al.
A Combination Therapy with Baicalein and Taxol Promotes Mitochondria-Mediated Cell Apoptosis: Involving in Akt/β-Catenin Signaling Pathway.
DNA Cell Biol. 2016; 35(11):646-656 [PubMed] Related Publications
Baicalein, a major flavonoid, possesses anticancer and anti-inflammatory activity. The aim of the study is to explore the efficiency of combination therapy with baicalein and taxol, as well as the molecular mechanism on antitumor activity. Human ovarian cancer cells were treated with different concentration of baicalein for 48 h, and cell viability was determined by MTT assay. Baicalein inhibited cell proliferation of ovarian cancer cells, and IC50 value of baicalein in A2780 cells, SKOV3 cells, and OVCAR cells was 46.23, 60.68, and 38.03 μM, respectively. The ovarian cancer cells were treated with 10 μM of baicalein combined with increasing concentration of taxol for 48 h, and the results demonstrated that combination therapy with baicalein and taxol had much higher antitumor effects compared with the monotherapy. The molecular mechanisms involving in combination therapy promoted the caspase-3 activity then leading to cleavage of poly-ADP-ribose polymerase, which increased the cell apoptosis of ovarian cancer cells. Moreover, Z-VAD-FMK treatment partially decreased the baicalein-induced proliferation inhibition in human ovarian cancer cells. Furthermore, baicalein induced apoptosis through activation of the activities of caspase-3,-9, and increased cytoplasmic cytochrome C release. Importantly, baicalein inhibited the growth of A2780 cells by inhibiting Akt/β-catenin signaling pathway. In conclusion, our result revealed that baicalein combinated with taxol at low concentrations could exert synergistic antitumor effects in ovarian cancer cells through mitochondria-mediated cell apoptosis and Akt/β-catenin signaling pathway. Baicalein has a promising potential to be developed as an antitumor compound, and combination therapy of baicalein and taxol exhibits an antitumor potential in clinical therapy for human ovarian cancers.

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