Nsc23925 prevents the development of paclitaxel resistance by inhibiting the introduction of P‐glycoprotein and enhancing apoptosis

Abstract

Strategies to prevent the emergence of drug resistance will increase the effectiveness of chemotherapy treatment and prolong survival of women with ovarian cancer. The aim of the current study is to determine the effects of NSC23925 on preventing the development of paclitaxel resistance in ovarian cancer both in cultured cells in vitro and in mouse xenograft models in vivo, and to further elucidate these underlying mechanisms. We first developed a paclitaxel-resistant ovarian cancer cell line, and demonstrated that NSC23925 could prevent the introduction of paclitaxel resistance by specifically inhibiting the overexpression of Pgp in vitro. The paclitaxel-resistant ovarian cancer cells were then established in a mouse model by continuous paclitaxel treatment in combination with or without NSC23925 administration in the mice. The majority of mice continuously treated with paclitaxel alone eventually developed paclitaxel resistance with overexpression of Pgp and anti-apoptotic proteins, whereas mice remained sensitivity to paclitaxel and displayed lower expression levels of Pgp and anti-apoptotic proteins after administered continuously with combination paclitaxel-NSC23925. Paclitaxel-NSC23925 treated mice experienced significantly longer overall survival time than paclitaxel-treated mice. Furthermore, the combination of paclitaxel and NSC23925 therapy did not induce obvious toxicity as measured by mice body weight changes, blood cell counts, and histology of internal organs. Collectively, our observations provide evidence that NSC23925 in combination with paclitaxel may prevent the onset of Pgp or anti-apoptotic-mediated paclitaxel resistance, and improve the long-term clinical outcome in patients with ovarian cancer.

NVP‐TAE684 reverses multidrug resistance (MDR) in human osteosarcoma by inhibiting P‐glycoprotein (PGP1) function

“…The identification and development of specific and potent inhibitors of PGP1 for clinical use in combination with conventional chemotherapy appears to be a promising area in the field of novel anticancer therapeutics in reversing drug resistance (Duan et al, ; Ferry et al, ; Luetke et al, ; Yang et al, ). In this study, we identified NVP‐TAE684 as one of the most effective MDR reversing agents, after screening 500+ compounds from a pre‐selected, kinase‐directed small molecule library.…”

“…The mouse monoclonal antibody to human actin was purchased from Sigma‐Aldrich. Western blot analysis was performed as previously described (Yang et al, ). The levels of expressed proteins were visualized by scanning the membrane on an Odyssey Infrared Imaging System (LI‐COR Biosciences, Lincoln, NE, USA) with both 680 and 800 nm channels.…”

Band gap and electronic structure of MgSiN2 determined using soft X‐ray spectroscopy and density functional theory

“…The distribution of the Si and N pDOS resembles that of other nitridosilicates composed of [SiN 4 ] tetrahedra. In β-Si 3 N 4 , which is composed only of [SiN 4 ] tetrahedra and has similar Si-N distances, the VB spectral weight is similarly distributed in two spectral ranges with similar widths and separations [58,59]. In MSiN 2 nitridosilicates with larger cations (M = Sr, Ba) the Si and N spectral weight is similar in shape, but the width of the valence bands are broadened [15].…”

Role of 5‑Aza‑CdR in mitomycin‑C chemosensitivity of T24 bladder cancer cells

“…The clinical significance of P-gp and MRP1 in drug resistance is supported by evidence that their expression indicates an adverse prognosis in patients with a range of types of cancer (11,12). Yang et al (13) demonstrated that Nsc23925 could prevent the development of paclitaxel resistance by inhibiting the expression of P-gp and enhancing apoptosis. Therefore, it was concluded from the data of the present study that 5-Aza-CdR enhances MMC chemosensitivity of T24 cells by suppressing P-gp and MRP1 expression.…”