Synergistic effect of bromocriptine and tumor necrosis factor-α on reversing hepatocellular carcinoma multidrug resistance in nude mouse MDR1 model of liver neoplasm

Abstract

Abstract Abstract Abstract AIM:To investigate the effect of bromocriptine (BCT) and tumor necrosis factor-α (TNF-α) on hepatocellular carcinoma (HCC) multidrug resistance (MDR) in nude mouse MDR model of liver neoplasm. METHODS:Human hepatocarcinoma cell line HepG 2 , drug resistant hepatocarcinoma cell line HepG 2 /adriamycin (ADM) and hepatocarcinoma cell line transfected with TNF-α gene HepG 2 /ADM/TNF were injected into the liver of nude mice via orthotopic implantation and MDR model of liver neoplasm in vivo was established (HepG 2 , ADM, TNF, BCT groups). Among these groups, BCT group and TNF group were treated with BCT through gastric canal. Each group was divided into control group and chemotherapy group. Size and weight of the tumor were measured. Furthermore, tumor histological character and growth of the nude mice were observed and their chemosensitivity was tested. MDR-associated genes and proteins (MRP, LRP) of implanted tumors were detected by immunohistochemistry, reverse transcriptase polymerase chain reaction, and apoptosis rate of hepatocarcinoma cells was detected by TUNEL assay. RESULTS:The nude mouse model of each cell line was inoculated successfully. The tumor growth rate and weight were significantly different among groups. After chemotherapy, abdominal cavity tumor growth inhibition rate was higher in BCT group (67%) compared to ADM and TNF groups, and similar to HepG 2 group (54%). MDR1 and LRPmRNA could be detected in all groups, but TNF-α was detected only in TNF and BCT groups. Furthermore, MDR1 and LRP protein expression of tumors in TNF and BCT groups was low similar to HepG 2 group. The apoptosis rate of hepatocarcinoma cells was much higher in BCT group than in other groups with TUNEL assay.

Chemosensitization by diverging modulation by short-term and long-term TNF-α action on ABCB1 expression and NF-κB signaling in colon cancer

“…Consistent with the pre-clinical findings of cytokine-mediated chemosensitization, clinical trials have demonstrated synergism of combinations of cytostatic drugs with TNF-α or interferones in cancer patients (14,15). Among all cytokines used for ABCB1 expression modulation, TNF-α has shown the highest efficiency in vitro, in vivo and in clinical approaches (9,11,13,16). Although the TNF-α mediated effects on ABCB1 expression were repeatedly shown at functional level, it is still not fully understood, what mechanism in cell signalling is reponsible for these effects.…”

“…Among these approaches the use of cytokines has shown promise for downregulation of ABCB1 in association with increased drug uptake and chemosensitization of tumor cells (5). Several studies have shown, that cytokines, such as tumor necrosis factor α (TNF-α), interferon γ (IFN-γ), leukoregulin and interleukin-2 (IL-2) are capable of reducing ABCB1 gene expression and increasing chemosensitivity of different cancer cell lines in vitro, and more recently also for endothelial cells in the blood-brain barrier (6)(7)(8)(9)(10)(11)(12). It has been shown, that particularly persistent treatment with these cytokines is of importance to achieve significant reduction in ABCB1 gene expression (6,7,9,13).…”

“…Several studies have shown, that cytokines, such as tumor necrosis factor α (TNF-α), interferon γ (IFN-γ), leukoregulin and interleukin-2 (IL-2) are capable of reducing ABCB1 gene expression and increasing chemosensitivity of different cancer cell lines in vitro, and more recently also for endothelial cells in the blood-brain barrier (6)(7)(8)(9)(10)(11)(12). It has been shown, that particularly persistent treatment with these cytokines is of importance to achieve significant reduction in ABCB1 gene expression (6,7,9,13). Consistent with the pre-clinical findings of cytokine-mediated chemosensitization, clinical trials have demonstrated synergism of combinations of cytostatic drugs with TNF-α or interferones in cancer patients (14,15).…”

Radiation- and Chemoinduced Multidrug Resistance in Colon Carcinoma Cells

“…As glutathione is essential for detoxification, the catalytic subunit of glutamate-cysteine ligase (GCLC) was monitored, as well as glutathione-S-transferase (GST). Published primers were chosen for GAPDH, MDR1, MRP1, MRP2, MRP3, GST [30], LRP [8], and GCLC [25]. Primers are summarized in Table 1.…”

How to overcome multidrug resistance in chemotherapy for advanced hepatocellular carcinoma

“…In addition, TNF‐α combined with cytotoxic agents has been proven to enhance the sensitivity to anti‐cancer treatments in many tumours. Combination with bromocriptine and TNF‐α also reversed HCC MDR in a model of liver neoplasm (16).…”