Therapeutic potential of thalidomide for gemcitabine-resistant bladder cancer

Abstract

Controversial effects of thalidomide for solid malignancies have been reported. In the present study, we evaluate the effects of thalidomide for transitional cell carcinoma (TCC), the most common type of bladder cancer. Thalidomide precipitates were observed when its DMSO solution was added to the culture medium. No precipitation was found when thalidomide was dissolved in 45% γ-cyclodextrin, and this concentration of γ-cyclodextrin elicited slight cytotoxicity on TCC BFTC905 and primary human urothelial cells. Thalidomide-γ-cyclodextrin complex exerted a concentration-dependent cytotoxicity in TCC cells, but was relatively less cytotoxic (with IC50 of 200 µM) in BFTC905 cells than the other 3 TCC cell lines, possibly due to upregulation of Bcl-xL and HIF-1α mediated carbonic anhydrase IX, and promotion of quiescence. Gemcitabine-resistant BFTC905 cells were chosen for additional experiments. Thalidomide induced apoptosis through downregulation of survivin and securin. The secretion of VEGF and TNF-α was ameliorated by thalidomide, but they did not affect cell proliferation. Immune-modulating lenalidomide and pomalidomide did not elicit cytotoxicity. In addition, cereblon did not play a role in the thalidomide effect. Oxidative DNA damage was triggered by thalidomide, and anti-oxidants reversed the effect. Thalidomide also inhibited TNF-α induced invasion through inhibition of NF-κB, and downregulation of effectors, ICAM-1 and MMP-9. Thalidomide inhibited the growth of BFTC905 xenograft tumors in SCID mice via induction of DNA damage and suppression of angiogenesis. Higher average body weight, indicating less chachexia, was observed in thalidomide treated group. Sedative effect was observed within one-week of treatment. These pre-clinical results suggest therapeutic potential of thalidomide for gemcitabine-resistant bladder cancer.

Overexpression of ubiquitin specific proteases 44 promotes the malignancy of glioma by stabilizing tumor-promoter securin

“…Although some researchers argued whether securin is necessary for mitosis in certain cells, the fact regarding securin as oncoprotein is indubitable [ 16 – 18 ]. The high expression level of securin appears in breast cancer, lung cancer, and bladder cancer, and it is widely involved in malignant proliferation, invasion, and angiopoiesis [ 19 – 21 ]. According to the published data, securin also serves as a tumor-promoter in glioma, and the overexpression of securin in high-grade glioma heraldes the bad prognosis [ 18 , 22 ].…”

Preparation, characterization, in vitro and in vivo anti-tumor effect of thalidomide nanoparticles on lung cancer

“…30,31 THA has been found to exhibit preventative and therapeutic effects in various cancer species and has been confirmed to be a potent chemosensitizer. 9,32 However, due to the extreme hydrophobicity and degradation characteristics exhibited by this compound in vivo, the use of THA is vastly limited and THA may not be administered via the intravenous route. Furthermore, the poor water solubility of THA limits the delivery characteristics of the drug to the tumor site at an effective concentration.…”

“…[5][6][7][8] So far, worldwide studies on THA intervention in malignant tumors, including hematological malignancy and solid tumors, such as lung cancer, bladder cancer, pancreatic carcinoma, and hepatocellular carcinoma, have been reported. [9][10][11][12][13][14] However, due to several physical properties of THA, including insolubility in water, no parenteral preparation is available and the overall applicability vastly restricted. 15 In recent years, nanotechnology has been developed as an important scientific field that now attracts a significant amount of attention in drug delivery and cancer therapy.…”

Effects of thalidomide on growth and VEGF-A expression in SW480 colon cancer cells

“…Another in vitro study on ovarian cancer also reported that THD was able to inhibit the proliferation of ovarian cancer cells SKOV3 (36), which suggested that THD may have a role in promoting anti-tumor effects by directly inhibiting proliferation. On the other hand, THD was also able to promote the apoptosis of transitional cell carcinoma cells (37).…”