Re-positioning of low dose paclitaxel against depressive-like behavior and neuroinflammation induced by lipopolysaccharide in rats: Crosstalk between NLRP3/caspase-1/IL-1ß and Sphk1/S1P/ NF-κB signaling pathways.

AIMS: Depression is a potentially fatal illness affecting millions of individuals worldwide, across all age groups. Neuroinflammation is a key factor in depression development. Paclitaxel (PXL), a well-known chemotherapeutic agent has been used as therapy for several types of cancer. This study aims to evaluate the ameliorative effect of low-dose PXL against lipopolysaccharide (LPS)-induced depression in rats. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were administrated a single dose of LPS (5 mg/kg, i.p.); 2 h later, rats received PXL (0.3 mg/kg, i.p. three times/week) for one week. KEY FINDINGS: Low-dose PXL alleviated LPS-induced depressive-like behavior in rats as evidenced by significantly improving behavioral changes in both forced swim test (FST) and open field test (OFT), successfully mitigated depletion of monoamines (serotonin, norepinephrine, and dopamine), in addition to markedly decreasing lipid peroxidation with antioxidant levels elevation in brain tissues. Low-dose PXL substantially decreased inflammation triggered by LPS in brain tissue via repressing the expression of NLRP3 and its downstream markers level, caspase-1 and IL-1ß jointly with a corresponding decrease in proinflammatory cytokine levels (TNF-α). Furthermore, low-dose PXL remarkably down-regulated Sphk1/S1P signaling pathway. Concurrent with these biochemical findings, there was a noticeable improvement in the brain tissue's histological changes. SIGNIFICANCE: These findings prove the role of low-dose PXL in treatment of LPS-induced neuroinflammation and depressive-like behavior through their anti-depressant, antioxidant and anti-inflammatory actions. The suggested molecular mechanism may entail focusing the interconnection among Sphk1/S1P, and NLRP3/caspase-1/IL-1ß signaling pathways. Hence PXL could be used as a novel treatment against LPS-induced depression.

Vitamin E-rich Nanoemulsion Enhances the Antitumor Efficacy of Low-Dose Paclitaxel by Driving Th1 Immune Response.

PURPOSE: To overcome the drawbacks of high dose regimen and improve the outcomes of chemotherapy at a low dose, an immunotherapeutic nanoemulsion based combination of chemotherapeutic agent (paclitaxel) with immunomodulatory agent (vitamin E) was developed and evaluated for their antitumor effect against breast cancer. METHODS: A total of five nanoemulsions loaded with various content of vitamin E were prepared and characterized. The immunoregulatory effects of vitamin E along with the overall antitumor efficacy of vitamin E-rich nanoemulsion with a low dose of paclitaxel were investigated through in vitro and in vivo experiments. RESULTS: Vitamin E-rich nanoemulsion exhibited relatively narrow size distribution, high entrapment efficiency and controlled in vitro release profile. In RAW264.7 cells, vitamin E-rich nanoemulsion significantly enhanced the secretion of Th1 cytokines and down-regulated the secretion of Th2 cytokine. In a co-culture system, vitamin E-rich nanoemulsion induced a high apoptosis rate in MDA-MB-231 cells as compared with vitamin E-low nanoemulsion. Furthermore, vitamin E-rich nanoemulsion exhibited superior in vivo antitumor efficacy in comparison with Taxol and vitamin E-low nanoemulsion at a paclitaxel dose of 4 mg/kg. CONCLUSIONS: Vitamin E-rich nanoemulsion has great potential for the treatment of breast cancers with a low dose of paclitaxel via driving Th1 immune response.

Phase I study of weekly palliative chemotherapy with low-dose third-line paclitaxel for biliary tract cancer.

The prognosis of patients with unresectable and recurrent biliary tract cancer (BTC) is very poor. Although gemcitabine (GEM) plus cisplatin therapy is useful for unresectable cases, the median overall survival (OS) of the patients is <1 year, and third-line chemotherapy following failure of 5-fluorouracil (5-FU) and GEM plus cisplatin is currently unavailable. The clinical efficacy and basic effects of low-dose paclitaxel (PTX) therapy for patients with BTC was previously reported. We herein present the results of a phase I clinical trial of weekly low-dose PTX as third-line palliative chemotherapy. PTX was administered on days 1, 8, 15 and 22 of each cycle and repeated twice as follows: Level 1, 40 mg/m2; level 2, 50 mg/m2 (n=3). During the two cycles, grade 1 or 2 adverse events were observed in 3 patients, whereas dose-limiting adverse events (grade 3 or 4) were not observed. The disease control rate was 83.3% (partial response, n=3; stable disease, n=2). The OS and median survival were 15.4 and 9.0 months, respectively. In conclusion, palliative chemotherapy with low-dose PTX following failure of GEM and 5-FU was well-tolerated, safe and effective for patients with unresectable or recurrent BTCs, and the optimal dose was 50 mg/m2.