| In vitro: |
| J Surg Res. 2015 Apr;194(2):622-30. | | Antitumor activity of paclitaxel is significantly enhanced by a novel proapoptotic agent in non-small cell lung cancer.[Pubmed: 25498514] | Newer targeted agents are increasingly used in combination chemotherapy regimens with enhanced survival and improved toxicity profile. Taxols, such as Paclitaxel, independently potentiate tumor destruction via apoptosis and are used as first line therapy in patients with advanced non-small cell lung cancer (NSCLC). Procaspase-3-activating compound-1 (PAC-1) is a novel proapoptotic agent that directly activates procaspase-3 (PC-3) to caspase-3, leading to apoptosis in human lung adenocarcinoma cells. Hence, we sought to evaluate the antitumor effects of Paclitaxel in combination with PAC-1.
METHODS AND RESULTS:
Human NSCLC cell lines (A-549 and H-322m) were incubated in the presence of PAC-1 and Paclitaxel. Tumor cell viability was determined by a tetrazolium-based colorimetric assay (MTT assay). Western blot and flow cytometric analysis were performed to evaluate expression of PC-3 and the proportion of apoptotic cells, respectively. A xenograft murine model of NSCLC was used to study the in vivo antitumor effects of PAC-1.
PAC-1 significantly reduced the inhibitory concentration 50% of Paclitaxel from 35.3 to 0.33 nM in A-549 and 8.2 to 1.16 nM in H-322m cell lines. Similarly, the apoptotic activity significantly increased to 85.38% and 70.36% in A-549 and H322m, respectively. Significantly enhanced conversion of PC-3 to caspase-3 was observed with PAC-1 Paclitaxel combination (P < 0.05). Mice treated with a drug combination demonstrated 60% reduced tumor growth rate compared with those of controls (P < 0.05).
CONCLUSIONS:
PAC-1 significantly enhances the antitumor activity of Paclitaxel against NSCLC. The activation of PC-3 and thus the apoptotic pathway is a potential strategy in the treatment of human lung cancer. | | Am J Cancer Res . 2017 Apr 1;7(4):903-912. | | Lenvatinib enhances the antitumor effects of paclitaxel in anaplastic thyroid cancer[Pubmed: 28469962] | | Abstract
Anaplastic thyroid cancer (ATC) is a rare malignancy and has a very poor prognosis due to its aggressive behavior and resistance to treatment. No effective treatment modalities are currently available. Lenvatinib has shown encouraging results in the patients with radioiodine-refractory differentiated thyroid cancer (DTC); however, lenvatinib monotherapy has a relatively low efficacy against ATC. In this study, we assessed the antitumor effects of a combination of lenvatinib and microtubule inhibitor Paclitaxel in ATC cells in vitro and in vivo. Our data showed that lenvatinib monotherapy was less effective than Paclitaxel monotherapy in ATC cell lines and xenografts. The addition of lenvatinib to Paclitaxel synergistically inhibited colony formation and tumor growth in nude mice, and induced G2/M phase cell cycle arrest and cell apoptosis as compared to lenvatinib or Paclitaxel monotherapy. Taken together, this is the first study to suggest that lenvatinib/Paclitaxel combination may be a promising candidate therapeutic strategy for ATC.
Keywords: Thyroid cancer; antitumor effects; combined therapy; lenvatinib; Paclitaxel. |
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| In vivo: |
| Laryngoscope. 2015 May;125(5):1175-82. | | Investigation of protective role of curcumin against paclitaxel-induced inner ear damage in rats.[Pubmed: 25583134] | The aim of this study was to investigate the potential protective effect of curcumin on Paclitaxel-induced ototoxicity in rats by means of immunohistochemical and histopathological analysis and distortion product otoacoustic emissions (DPOAEs).
METHODS AND RESULTS:
Forty Sprague-Dawley rats were randomized into five groups. Group 1 was administered no Paclitaxel and curcumin during the study. Groups 2, 3, 4 and 5 were administered 5 mg/kg Paclitaxel; 200 mg/kg curcumin; 5 mg/kg Paclitaxel, followed by 200 mg/kg curcumin; 200 mg/kg curcumin and a day later 5 mg/kg Paclitaxel followed intraperitoneally by 200 mg/kg curcumin once a week for 4 consecutive weeks, respectively. After the final DPOAEs test, the animals were sacrificed and their cochlea were prepared for hematoxylin and eosin and caspase-3 staining. The DPOAEs thresholds and histopathological and immunohistochemical findings were substantially correlated in all groups. The histopathologic findings in the cochlea of the Paclitaxel-treated animals showed not only changes in the organ of Corti, but also damage to the stria vascularis and spiral limbus, including nuclear degeneration, cytoplasmic vacuolization, and atrophy of intermediate cells. Additionally, cochlear changes in group 2, such as intense apoptosis, were confirmed by caspase-3 immunohistochemical staining. In group 4, coreceiving curcumin could not sufficiently prevent Paclitaxel-induced ototoxicity, and the results in group 5 were similar to the control group.
CONCLUSIONS:
In our study, we have concluded that pre- and coreceiving curcumin can significantly protect the cochlear morphology and functions on Paclitaxel-induced ototoxicity in rats. Curcumin might be considered as a potential natural product that, used as a dietary supplement, could be easily given to patients undergoing Paclitaxel chemotherapy. | | FEBS J . 2016 Aug;283(15):2836-52. | | Low doses of paclitaxel enhance liver metastasis of breast cancer cells in the mouse model[Pubmed: 27307301] | | Abstract
Paclitaxel is the most commonly used chemotherapeutic agent in breast cancer treatment. In addition to its well-known cytotoxic effects, recent studies have shown that Paclitaxel has tumor-supportive activities. Importantly, Paclitaxel levels are not maintained at the effective concentration through one treatment cycle; rather, the concentration decreases during the cycle as a result of drug metabolism. Therefore, a comprehensive understanding of Paclitaxel's effects requires insight into the dose-specific activities of Paclitaxel and their influence on cancer cells and the host microenvironment. Here we report that a low dose of Paclitaxel enhances metastasis of breast cancer cells to the liver in mouse models. We used microarray analysis to investigate gene expression patterns in invasive breast cancer cells treated with low or clinically relevant high doses of Paclitaxel. We also investigated the effects of low doses of Paclitaxel on cell migration, invasion and metastasis in vitro and in vivo. The results showed that low doses of Paclitaxel promoted inflammation and initiated the epithelial-mesenchymal transition, which enhanced tumor cell migration and invasion in vitro. These effects could be reversed by inhibiting NF-κB. Furthermore, low doses of Paclitaxel promoted liver metastasis in mouse xenografts, which correlated with changes in estrogen metabolism in the host liver. Collectively, these findings reveal the paradoxical and dose-dependent effects of Paclitaxel on breast cancer cell activity, and suggest that increased consideration be given to potential adverse effects associated with low concentrations of Paclitaxel during treatment. |
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