Acquired platinum resistance enhances tumour angiogenesis through angiotensin II type 1 receptor in bladder cancer

Abstract

Background:We investigated the changes in reactive oxygen species (ROS) and angiogenesis through angiotensin II (Ang II) type 1 receptor (AT1R) after the development of acquired platinum resistance in bladder cancer.Methods:Four invasive human bladder cancer cell lines, T24, 5637, T24PR, and 5637PR, were used in vitro, whereas in vivo, T24 and T24PR cells were used. T24PR and 5637PR cells were newly established at our institution as acquired platinum-resistant sublines by culturing in cisplatin (CDDP)-containing conditioned medium for 6 months.Results:Ang II induced significantly higher vascular endothelial growth factor (VEGF) production in T24PR and 5637PR cells than in their corresponding parent cells in vitro, whereas Ang II induced a further increase in VEGF production. These platinum-resistant cells also showed significantly higher AT1R expression than their corresponding parent cells. ROS was also significantly upregulated in T24PR and 5637PR cells, whereas increased AT1R expression was significantly downregulated by scavenging free radicals. We also demonstrated the efficacy of AT1R blockade at suppressing the growth of platinum-resistant xenograft model.Conclusion:Our findings indicate a new molecular mechanism for upregulated AT1R signalling through increased ROS when tumours progressed after the CDDP-based regimens, and shed light on the importance of AT1R blockade for platinum-resistant bladder cancers.

Nicotine Induces Tumor Growth and Chemoresistance through Activation of the PI3K/Akt/mTOR Pathway in Bladder Cancer

“…As shown in Figs. 2A and 4A, we found that the inhibitory effect of 5 mg/kg of CDDP or 40 mg/kg of NVP-BEZ235 was significant (28)(29)(30) and then selected doses of CDDP and NVP-BEZ235 of 2 and 12.5 mg/kg, respectively, for the experiment of their combination study in nicotine-exposed T24 tumor-bearing mice. In nicotine-exposed T24 tumor-bearing mice, on day 21, tumor volume in mice treated with 2 mg/kg of CDDP (1,218.4 AE 116.0 mm 3 ) was not significantly different from that treated with vehicle control (1,299.5 AE 126.5 mm 3 , P ¼ 0.643, Fig.…”

Analysis of cabazitaxel‐resistant mechanism in human castration‐resistant prostate cancer

“…These results ensure that our cell line models have significant resistance to CBZ. We previously reported on cisplatin‐resistant urothelial cancer cell lines, which had an IC 50 3 times higher than parental cells . Xenograft tumors of these cell lines also grew to twice the size of that of their parental cell lines.…”

Acquired platinum resistance involves epithelial to mesenchymal transition through ubiquitin ligase FBXO32 dysregulation

“…We previously reported 2 different UC cell lines with acquired platinum resistance established in our laboratory, T24PR (platinum resistant) and 5637PR (25). In preliminary studies, we observed that these cell lines had an altered phenotype consistent with EMT, and exhibited a marked difference in migratory potential before and after acquired platinum resistance.…”

“…Two UC cell lines (T24 and 5637) were obtained from the American Type Culture Collection, and T24PR and 5637PR cells were established in our laboratory as sublines of T24 and 5637 with acquired platinum resistance (25). Briefly, T24 and 5637 cells were grown and passaged upon reaching confluence in medium containing CDDP over a 6-month period to develop platinum resistance, with a gradual increase in CDDP concentration to 3 μM.…”