Expression of multidrug resistance-associated proteins in paediatric soft tissue sarcomas before and after chemotherapy

Abstract

Abstract. Expression of multidrug resistance (MDR) proteins is thought to significantly contribute to the different biological/ clinical behaviour of soft tissue sarcomas (STS) of various histological types and clinicopathological stages, as they are responsible for active efflux of cytotoxic drugs from tumour cells. We investigated the expression of 3 MDR proteins, i.e., permeability glycoprotein 1 (P-gp), multidrug resistance-associated protein 1 (MRP1) and multidrug resistance 3 (MDR3), in 43 STS specimens from newly-diagnosed paediatric patients, 31 with rhabdomyosarcoma (RMS) and 12 with non-RMS STS. To assess the influence of chemotherapy on STS drug resistance, the number of MDR-associated protein-positive cells was determined in 15 patients on both primary lesions before chemotherapy and on residual tumour after chemotherapy. At least one of the MDR-associated proteins tested was detected in 84% of primary untreated STS specimens. In these specimens, MRP1 was detected in a high percentage (70%) of the cases, followed by MDR3 in 58% and P-gp in 44%. Many specimens showed co-expression of two different MDR proteins. Interestingly, MDR3 was significantly associated with the presence of PAX3/ PAX7-FKHR transcripts in RMS (p<0.05). Moreover, expression of MRP1 and MDR3 was significantly more frequent in group III and IV tumours as compared with those of groups I and II (p<0.01). After chemotherapy MRP1, MDR3 and, to a lesser extent, P-gp expression was found to be increased in most of the samples. The frequent expression of these MDR-associated proteins in primary tumour cells before chemotherapy and the increase of their levels after chemotherapy, suggest that these proteins play a pivotal role in conferring drug resistance and in producing therapy-induced differentiation on STS.

Multidrug resistance transporter profile reveals MDR3 as a marker for stratification of blastemal Wilms tumour patients

“…For MRP1 , high levels of the gene were associated with poor prognosis and high histological grade in childhood neuroblastoma [40–42], soft tissue sarcoma [43], and non-small cell lung cancer [44–46], and with recurrence in breast cancer patients who were treated with chemotherapy [47]. To our knowledge, only one previously reported study suggested the existence of a common expressing regulatory mechanism between MDR3 and MRP1 in high-risk tumours such as breast cancers and nephroblastoma [48]. …”

“…Resistance to chemotherapy may be due to high expression of multidrug resistance mechanisms already present in tumor cells before treatment, and/or it is also possible that chemotherapy modulates the expression of multidrug resistance proteins reducing treatment efficacy. Several studies showing that expression of MRP1 and MDR3, among others multidrug resistance genes may induce or increase after chemotherapy in pediatric tumors, soft tissue sarcomas and malignant melanoma [33, 48, 55]. In the SIOP-93-01 protocol, vincristine and actinomycin D treatment were given to the patient with localized tumor, and doxorubicin was included in patients with metastatic disease.…”

Overexpression of ABCB4 contributes to acquired doxorubicin resistance in breast cancer cells in vitro

“…In some types of cell lines, e.g., doxorubicin-resistant LoVo cells, ABCB4 expression was increased to a higher degree than ABCB1 expression, which suggesting that the predominant transporter that was responsible for doxorubicin resistance may be ABCB4 [16]. A marked increase of ABCB4 expression was also found in surgical specimens from patients with soft-tissue sarcomas and Wilms tumour after chemotherapy [17,18]. However, the exact role of ABCB4 in doxorubicin resistance is still unknown.…”

“…It has been confirmed that ABCB4 can also act as an efflux transporter to limiting the intracellular accumulation of drugs such as digoxin, paclitaxel, daunorubicin, vinblastine, and ivermectin [13]. Recently, accumulating evidence indicates that ABCB4 is overexpressed in cancer cells after exposure to some chemotherapeutic drugs including doxorubicin [14][15][16][17][18], which implicate the involvement of ABCB4 in the acquired resistance to these anticancer agents. However, the exact role of ABCB4 in doxorubicin resistance as well as the potential mechanisms still remains unclear.…”

<p>Management of Refractory Pediatric Sarcoma: Current Challenges and Future Prospects</p>

“…Clonal selection of MDR protein-expressing tumour cells and up-regulation of MDR proteins were thought to be the possible explanations for increased expression of MDR proteins in post-treatment specimens. 45 Serum and glucocorticoid inducible kinase expression in RMS has been shown to be associated with treatment resistance in RMS cell lines. 46 In vitro and in vivo studies in RMS have shown that GST mediates chemotherapy resistance.…”