Enhancement of the Efficacy of Chemotherapy for Lung Cancer by Simultaneous Suppression of Multidrug Resistance and Antiapoptotic Cellular Defense

Abstract

The efficacy of chemotherapy of lung cancer is limited by the development of resistance in cancer cells during treatment. In most lung cancers, this resistance is associated with the overexpression of (a) multidrug resistance-associated protein (MRP) responsible for drug efflux from the cancer cells (pump resistance) and (b) BCL2 protein that activates antiapoptotic cellular defense (nonpump resistance). A novel liposomal proapoptotic anticancer drug delivery system was developed to enhance anticancer efficacy of the well-established drug doxorubicin (DOX). This multicomponent drug delivery system was tested on multidrug-sensitive and -resistant human small-cell lung cancer cells. The drug delivery system includes four components: (a) liposome as a carrier, (b) DOX as an inductor of apoptosis, (c) antisense oligonucleotides (ASOs) targeted to MRP1 mRNA as a suppressor of pump resistance, and (d) ASOs targeted to BCL2 mRNA as a suppressor of nonpump resistance. Intracellular internalization of ASOs and DOX; the influence of the proposed system on the expression of genes and proteins involved in the multidrug resistance, cytotoxicity, and apoptosis induction and antiapoptotic defense; and the activity of caspases were studied. It was found that the proposed liposomal delivery system successfully delivered ASOs and DOX to cell nuclei, inhibited MRP1 and BCL2 protein synthesis, and substantially increased the anticancer action of DOX by stimulating the caspase-dependent pathway of apoptosis in multidrug-resistant human lung cancer cells.

Inhibition of lung tumor growth by complex pulmonary delivery of drugs with oligonucleotides as suppressors of cellular resistance

“…Nonpump drug resistance is primarily attributed to the activation of antiapoptotic cellular defense, and BCL2 protein is a key player in this defense. Similarly to MRP1, the expression of BCL2 protein increases substantially after the treatment with anticancer drugs (19,20,23,(27)(28)(29).Consequently, it is logical to hypothesize that local pulmonary delivery of anticancer agents, combined with simultaneous suppression of pump and nonpump resistance, would be capable of substantially enhancing the efficacy of treatment of lung cancer and limiting adverse side effects of chemotherapy on healthy organs. To test this hypothesis, we designed and examined, in an orthotopic murine model of human lung cancer, a complex system that allows inhalation local delivery of an anticancer drug (DOX) combined with suppressors of pump and nonpump resistance (ASO targeted to MRP1 and BCL2 mRNA, respectively).…”

“…Nonpump drug resistance is primarily attributed to the activation of antiapoptotic cellular defense, and BCL2 protein is a key player in this defense. Similarly to MRP1, the expression of BCL2 protein increases substantially after the treatment with anticancer drugs (19,20,23,(27)(28)(29).…”

“…Two main mechanisms are responsible for the resistance of cancer cells against chemotherapy: pump and nonpump resistance (18)(19)(20)(21)(22)(23). Pump resistance is caused by membrane efflux pumps that decrease the anticancer drug concentration inside the cells.…”

“…It was found that, in most types of lung cancer cells, pump resistance does not depend on the expression of P-glycoprotein, the common drug efflux pump for most other types of cancer; rather, lung cancer cells overexpress proteins from the multidrug resistance-associated protein (MRP) family (24)(25)(26). Previously, we have shown that MRP1 transporter is expressed in untreated lung cancer cells and that this expression is upregulated after the treatment of cancer cells with an anticancer agent, doxorubicin (DOX) (19)(20)(21). Another protein from the MRP cluster, MRP2, is not expressed at detectable levels in untreated lung cancer cells, whereas treatment with DOX leads to overexpression of this protein (19)(20)(21).…”

“…Previously, we have shown that MRP1 transporter is expressed in untreated lung cancer cells and that this expression is upregulated after the treatment of cancer cells with an anticancer agent, doxorubicin (DOX) (19)(20)(21). Another protein from the MRP cluster, MRP2, is not expressed at detectable levels in untreated lung cancer cells, whereas treatment with DOX leads to overexpression of this protein (19)(20)(21). Nonpump drug resistance is primarily attributed to the activation of antiapoptotic cellular defense, and BCL2 protein is a key player in this defense.…”