Mitotane Enhances Cytotoxicity of Chemotherapy in Cell Lines Expressing a Multidrug Resistance Gene (mdr-1/P-Glycoprotein) which is also Expressed by Adrenocortical Carcinomas

Abstract

P-Glycoprotein (Pgp), product of the mdr-1 gene, is a 130- to 180-kDa plasma membrane phosphoglycoprotein which mediates multidrug resistance in cell culture by increasing efflux of the natural product chemotherapeutic agents. High levels of expression of mdr-1/Pgp are found in both the normal adrenal and adrenocortical cancers. By RNA in situ hybridization the expression in adrenocortical cancer is shown to be widely distributed. The present study demonstrates that decreased drug accumulation mediated by mdr-1/Pgp can be overcome by clinically achievable concentrations of mitotane (o,p'-DDD). The increase in drug accumulation with the addition of mitotane is due at least in part to a decrease in drug efflux and results in an increase in cytotoxicity when agents of the natural product class are used. This effect is observed in cells with a broad range of mdr-1/Pgp expression, including levels comparable to those found in most adrenocortical cancers. Similar increases in drug accumulation can be demonstrated in an unselected adrenocortical cancer cell line that expresses mdr-1/Pgp. The finding that multidrug resistance mediated by mdr-1/Pgp can be reversed by mitotane provides a rational basis for exploring the use of mitotane in combination with natural product chemotherapeutic agents in adrenocortical cancer.

A phase II trial of combination chemotherapy and surgical resection for the treatment of metastatic adrenocortical carcinoma

“…16,17 Furthermore, in vitro studies with the ACC cell line, H295, have demonstrated high levels of Pgp expression with evidence of a role for this protein in mediating drug efflux. 18 The high levels of Pgp expression and its demonstrated function as a drug efflux pump suggests that the treatment of ACC may benefit from the addition of a Pgp antagonist. Previous studies have shown that in vitro, mitotane can increase drug accumulation by decreasing drug efflux, resulting in enhanced cytotoxicity.…”

“…This effect has been observed in cell lines expressing Pgp, suggesting that mitotane interferes with Pgp function. 18,19 The current report describes the results of a Phase II study evaluating a multimodality approach in patients with metastatic ACC. The treatment strategy was comprised of daily mitotane (o.p.ЈDDD) with continuous infusion doxorubicin, vincristine, and etoposide that was administered preoperatively and postoperatively to patients with potentially resectable disease.…”

Cytotoxic activity of gemcitabine, alone or in combination with mitotane, in adrenocortical carcinoma cell lines

“…Finally, the possible interactions of mitotane with other antitumor agents, including the chemotherapeutic drugs commonly used for ACC treatment, are poorly explored. In this latter respect, mitotane has been shown to sensitize ACC cancer cells to ionizing radiation (Cerquetti et al, 2008) and to enhance cytotoxicity of chemotherapy by reversing P-glycoprotein-mediated multidrug resistance with a specific effect on the cell cycle (Bates et al, 1991). However, very few studies determined in vitro the activity of mitotane in combination with other chemotherapeutic agents used in ACC patients (Villa et al, 1999).…”

Management of adrenocortical carcinoma: a consensus statement of the Italian Society of Endocrinology (SIE)

“…Chemotherapy in combination with mitotane was used fol-lowing the concept that mitotane inhibits the MDR-1/Pglycoprotein, a multidrug resistance protein functioning as a drug efflux pump, widely expressed in ACC [148]. Chemotherapy drugs used alone or in combination in the treatment of advanced ACC patients include cisplatin, etopo-side, doxorubicin/adriamycin, vincristine, 5-fluorouracil, and streptozotocin [89,133,149,150].…”