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  • The occurrence of MDR in cancer

    2022-08-17

    The occurrence of MDR in cancer patients undergoing chemotherapy can be mimicked in the laboratory by culturing cancer Kaempferol receptor in the presence of chemotherapeutic drugs, thereby enforcing the evolution of acquired drug resistance. This has been described in multiple model systems including the rhabdomyosarcoma (RMS) cell line RD which develops resistance to VCR due to upregulation of p-glycoprotein [19]. In addition to p-glycoprotein, also several other ABC transporters have been found to be overexpressed in cancer cell lines cultured under selective pressure, including MRD-associated protein 1 (MRP1) [20].
    Material and methods
    Results
    Discussion By studying MDR in pediatric cancers, we identified Smac mimetics as novel substrates for p-glycoprotein. While this is the first report connecting the Smac mimetic BV6 with MDR, our conclusions are supported by two previous studies that have linked the activity of Smac mimetics to p-glycoprotein expression [24,25]. In this regard, the Smac mimetic T-3256336 developed by Takeda [26] has been described as a potential substrate for p-glycoprotein. In addition, birinapant and some other novel Smac mimetics have also been shown to display reduced activity in p-glycoprotein-expressing cells [24]. Drug exclusion by p-glycoprotein or related plasma membrane transporters may lead to inefficient IAP inhibition in cancer cells, in particularly in those cancers that have previously been exposed to chemotherapy and may have acquired high p-glycoprotein expression as resistance mechanism. Although Smac mimetics have extensively been studied in clinical trials, no Smac mimetic has so far been approved for cancer treatment [27]. Up until now, the limited clinical efficacy of Smac mimetics has mainly been attributed to the lack of a biomarker that could be used to preselect susceptible tumors. However, our study may provide an alternative explanation, as most clinical studies have been performed in patients that have previously received several rounds of chemotherapy, and hence the cancers may already display high p-glycoprotein expression levels. Interestingly, there have already been several approaches aiming at reducing the exclusion of Smac mimetics by p-glycoprotein. To this end, modification of T-325636 has resulted in less affinity for p-glycoprotein while retaining IAP-binding capacity [25]. In an alternative approach, the linear structures of Smac mimetics have been modified to macrocyclic structures, which has resulted in enhanced cellular activity in p-glycoprotein-expressing cells [24]. Taken together, these studies demonstrate that modifications of Smac mimetics can reduce the affinity for p-glycoprotein, retaining higher intracellular drug levels and better target inhibition in the context of multidrug-resistant cancers. However, so far none of the modified Smac mimetics with reduced affinity for p-glycoproteins has been tested in clinical studies. Inhibition of IAP proteins by Smac mimetics is often being discussed in the context of chemoresistant cancers and may represent a promising strategy to resensitize tumor cells to anticancer therapeutics. In this regard, it is worth noting that several reports have indicated high IAP expression levels in chemoresistant cells and have suggested a connection between high IAP levels and bad prognosis [28,29]. A study on multiple myeloma has shown particularly high IAP expression levels in cells that also express high p-glycoprotein upon chemotherapy and has identified high IAP expression levels as a marker for poor prognosis in chemotherapy-resistant cells [28]. Also, multidrug-resistant HL60 cells display higher cIAP2 levels than their parental counterparts [30]. While the link between IAPs and chemoresistance has been studied extensively [31,32], so far no mechanistic explanation has been provided for this association. Our findings showing that Smac mimetics are substrates for p-glycoprotein and hence limited in their ability to combat chemoresistance adds another layer of complexity to the field of IAP proteins.