Vitamin E succinate induced apoptosis and enhanced chemosensitivity to paclitaxel in human bladder cancer cells in vitro and in vivo

Abstract

There have been several studies on the antitumor activities of vitamin E succinate (a-TOS) as complementary and alternative medicine. In the present study, we investigated the cytotoxic effect of a-TOS and the enhancement of chemosensitivity to paclitaxel by a-TOS in bladder cancer. and 5637 bladder cancer cell lines were cultured in a-TOS and ⁄ or paclitaxel in vitro. Cell viability, flow cytometric analysis, and nuclear factor-kappa B (NF-jB) activity were analyzed. For in vivo therapeutic experiments, preestablished KU-19-19 tumors were treated with a-TOS and ⁄ or paclitaxel. In KU-19-19 and 5637 cells, the combination treatment resulted in a significantly higher level of growth inhibition, and apoptosis was significantly induced by the combination treatment. NF-jB was activated by paclitaxel; however, the activation of NFjB was inhibited by a-TOS. Also, the combination treatment significantly inhibited tumor growth in mice. In the immunostaining of the tumors, apoptosis was induced and proliferation was inhibited by the combination treatment. Combination treatment of a-TOS and paclitaxel showed promising anticancer effects in terms of inhibiting bladder cancer cell growth and viability in vitro and in vivo. One of the potential mechanisms by which the combination therapy has synergistic cytotoxic effects against bladder cancer may be that a-TOS inhibits NF-jB induced by chemotherapeutic agents. (Cancer Sci 2010; 101: 216-223) T he prognosis for patients with advanced or metastatic bladder cancer remains poor, with a median survival of approximately 12 months. Systemic chemotherapy is the only current modality that provides the potential for somewhat long-term survival in patients with advanced or metastatic bladder cancer. Methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) has been the most common treatment regimen for advanced or metastatic bladder cancer since the 1980s.(1) The M-VAC regimen has been reported to produce a complete response in approximately 20% of patients, although long-term disease-free survival is rare.(2) M-VAC, though superior to single agent therapy, is associated with significant toxicity (more than 20% of recipients experience neutropenic fever). These disappointing results have prompted a search for additional agents and multidrug combinations.Taxoids are microtubule disassembly inhibitors and represent a new class of agents for use in cancer chemotherapy. Recently, the use of paclitaxel or docetaxel, a semisynthetic taxane, has been started in clinical trials in patients with advanced bladder cancer. Paclitaxel has demonstrated substantial single-agent activity in the treatment of advanced or metastatic bladder cancer. (3,4) Paclitaxel in combination with gemcitabine has shown promise for the treatment of patients with M-VAC refractory bladder cancer.(5,6) Paclitaxel causes cell death by inhibiting depolymerization of tubulin with resultant arrest in cell cycle progression, particularly at the G2 ⁄ M interface.(7) Besides this function, it also possesses cell-killin...

The effect of dual-functional hyaluronic acid-vitamin E succinate micelles on targeting delivery of doxorubicin

“…The cytotoxicity of HA-VES copolymers could be attributed to the function of VES, which is to selectively induce apoptosis and inhibit the proliferation of tumor cells without any cytotoxic effects on normal cells. 25,28 Moreover, enhanced cytotoxicity was observed with increase of DS, especially of HA-VES12, due to more VES existing in high DS of HA-VES12. Therefore, synthetic copolymers of HA-VES with different DS have selective antitumor abilities and could exert antitumor effects.…”

“…25,26 VES, not other vitamin E derivatives, has anticancer properties against multiple cancer cells and nontoxic side effects on normal cells, due to increased generation of reactive oxygen species inducing membrane-destabilizing properties in the tumor cells by VES. [26][27][28] Based on the hydrophobicity and synergistic antitumor effects of VES, a functional copolymer, with VES as the hydrophobic group and HA as the hydrophilic part, has been designed which acts as a nanocarrier for the delivery of antitumor drugs. 29 In this study, to integrate CD44 receptor-mediated active targeting effects of HA and synergistic antitumor effects of VES, the copolymers of HA-ethylenediamine-VES (called HA-VES) with different degrees of substitution (DS) were synthesized.…”

The Role of Alpha Tocopheryl Succinate (α-TOS) as a Potential Anticancer Agent

“…Previous studies have also shown that α-TOS inhibits tumor cell growth by a variety of mechanisms, including DNA synthesis arrest, cell cycle blockade, induction of apoptosis, inhibition of tumor cell proliferation and differentiation, as well as inhibition of angiogenesis (24,29,(44)(45)(46). This analogue kills cells via apoptosis and affects expression of genes involved in cell proliferation and cell death in a sub-apoptotic manner during the cell cycle (23).…”

Matrix metalloproteinases-2/9-sensitive peptide-conjugated polymer micelles for site-specific release of drugs and enhancing tumor accumulation: preparation and in vitro and in vivo evaluation

“…It has been widely reported that α-TOS and its analogs possess anticancer properties against a wide variety of human cancer cells while remaining nontoxic to normal cells ( Figure S5). 17 Mi et al reported the synergistic effect of T2K and DTX. 23 The same conclusion could also be drawn from the cytotoxicity of DTX-loaded TGK micelles and T2K micelles (Figure 7).…”

“…16 Second, TPGS also acts as an anticancer agent inducing apoptosis and producing a synergistic effect with other anticancer agents. 17 d-α-Tocopherol succinate (α-TOS) and its analogs can induce reactive oxygen species generation, subsequently inducing apoptosis in cancer cells while being nontoxic toward normal cells. 18,19 TPGS has also been approved by the US Food and Drug Administarion as a safe pharmaceutical adjuvant used in drug formulation.…”