Abstract
Chemotherapy is an important strategy for the treatment of bladder cancer. However, the main problem limiting the success of chemotherapy is the development of multidrug resistance (MDR). To improve the management of bladder cancer, it is an urgent matter to search for strategies to reverse MDR. We chose three kinds of herbal medicines including ginsenoside Rh2, (-)-Epigallocatechin gallate (EGCG) and Tetramethylpyrazine (TMP) to detect their effects on bladder cancer. Reversal effects of these three herbal medicines for drug resistance in adriamycin (ADM)-resistant Pumc-91 cells (Pumc-91/ADM) were assessed by Cell Counting Kit-8 (CCK-8) cell proliferation assay system. The mechanisms of reversal effect for TMP were explored in Pumc-91/ADM and T24/DDP cells. After Pumc-91/ADM and T24/DDP cells were treated with TMP, cell cycle distribution analysis was performed by flow cytometry. The expression of MRP1, GST, BCL-2, LRP and TOPO-II was evaluated using quantitative real-time polymerase chain reaction (qRT-PCR), immunefluorescence assay and western blot. It was observed that TMP was capable of enhancing the cytotoxicity of anticancer agents on Pumc-91/ADM cells in response to ADM, however Rh2 and EGCG were unable to. The reversal effect of TMP was also demonstrated in T24/DDP cells. Moreover, the treatment with TMP in Pumc-91/ADM and T24/DDP cells led to an increased of G1 phase accompanied with a concomitant decrease of cell numbers in S phase. Compared to the control group, an obvious decrease of MRP1, GST, BCL-2 and an increase of TOPO-II were shown in TMP groups with a dose-dependency in mRNA and protein levels. However, there was no difference on LRP expression between TMP groups and the control group. TMP could effectively reverse MDR of Pumc-91/ADM and T24/DDP cells and its mechanisms might be correlated with the alteration of MRP1, GST, BCL-2 and TOPO-II. TMP might be a potential candidate for reversing drug resistance in bladder cancer chemotherapy.
Highlights
Bladder cancer is the most common cancer of the genitourinary tract in men [1]
After cells were treated with Rh2 (5– 100 μM), Epigallocatechin gallate (EGCG) (10–200 μM) and TMP (0–32 mM) for 24h, the increase of cell inhibition rate ranged from 2.1% to 58.7%, 2.2% to 67.7%, 2.4% to 56.9%, for 48h ranged from 3.3% to 61.9%, 4.4% to 69.4%, 6.4% to 60.9% and for 72h ranged from 8.5% to 65.2%, 5.5% to 71.9%, 6.6% to 62.9% in Pumc-91/ADM cells, respectively (Fig 2a, 2b and 2c)
We found that there was an obvious reversal effect of TMP among the three kinds of herbal medicines in Pumc-91/ADM cells (Fig 3c, S2 Table)
Summary
Bladder cancer is the most common cancer of the genitourinary tract in men [1]. The transurethral resection of bladder tumor (TURBT) is essential for non-muscle invasive bladder cancer treatment. Systemic chemotherapy is a reasonable alternative after surgery for patients with muscle invasive bladder cancers. Selection of cancer cells with one chemotherapeutic drug usually results in cross-resistance to other drugs with different cellular targets and structures. This phenomenon is known as multidrug resistance (MDR) [5]. The development of multidrug resistance in bladder cancer cells can severely impair the success of cancer systemic chemotherapy [6]. Due to the development of MDR, the treatment in bladder cancer with adriamycin, cisplatin or other agents often fails. The acquisition of MDR could be mediated via many mechanisms, including the increase in drug efflux, the decrease in drug influx, drug inactivation and alterations in the drug target, modification of cell cycle checkpoints and increased DNA damage repair and defective apoptotic pathways [7,8,9]
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