Effect of hemorrhagic shock on apoptosis and energy-dependent efflux system in the brain

Recent findings suggest that apoptosis, which contributes to neuronal damage after ischemic injury, may play a role in sequelae associated with severe blood loss. This study examined the effect of hemorrhage and resuscitation on the expression (in situ hybridization and computerized image analysis) of bcl-2 mRNA, which codes for a protein that inhibits apoptosis, and mdr1 mRNA, which codes for a glycoprotein marker for drug efflux from the brain. Anaesthetized rats were subjected to volume-controlled (15 mL/kg) hemorrhage followed by resuscitation with shed blood (BR) or nonresuscitated (NR); control animals had femoral artery cannulation only (SHAM). Following 24 hr blood loss, distinctly lower levels of bcl-2 gene expression were observed in dentate gyrus of NR rats (0.25 ± 0.04) as compared to SHAM rats (0.52 ± 0.07); suscitation with shed blood prevented this reduction (0.58 ± 0.05). Similar results were observed in cortex, striatum, and hypothalamus. Also, mdr1 mRNA levels were significantly reduced in all brain areas of the NR group as compared to the BR and SHAM groups. The findings suggest that blood resuscitation suppressed apoptosis and protected against loss of energy-dependent efflux system in the brain in response to hemorrhage.     

Plasmodium vivax: allele variants of the mdr1 gene do not associate with chloroquine resistance among isolates from Brazil, Papua, and monkey-adapted strains

We describe here the sequence of the Plasmodium vivax mdr1 gene from 10 different isolates differing in chloroquine sensitivity. The deduced amino acid sequence of PvMDR1 shares more than 70% similarity with other malarial MDR proteins and it displays consensus motifs of an ABC family transporter including two transmembrane domains and two ATP binding cassettes. Similarity and dendrogram analyses revealed that sequences could be grouped according to their geographical origin. Within each geographical group however, no correlation was found between chloroquine resistance and specific mutations.     

Circumvention of chemotherapy-induced myelosuppression by transfer of themdr1 gene

Drug-induced myelosuppression is a frequent reason for curtailing chemotherapy in cancer patients. Rescue of myelosuppressed patients with autologous marrow transplants is reasonably advanced and permits an increase in the dose of anticancer drugs. Despite this improvement, patients often relapse with drug resistance disease. The human multidrug resistance (mdr1) gene might make it possible to render hemopoietic stem cells resistant to anticancer drugs after transfer of this gene. By introducing resistant stem cells into patients it might be possible to treat these patients repeatedly with otherwise ablative therapy. This review explores the feasibility ofmdr1 gene therapy.Abbreviations MDR multidrug resistance - ABMT autologous bone marrow transplantation - P-gp P-glycoprotein - RCR replication-competent retrovirus     

Reversal of doxorubicin resistance by the amiloride analogue EIPA in multidrug resistant human colon carcinoma cells

Although multidrug resistance (mdr) may arise through a variety of mechanisms, the most widely studied and accepted form is associated with an increased concentration of P-glycoprotein (P-gp), a 170kd protein found in the membrane fraction of a number of mammalian cells. Since mdr seems to be related to the ability of resistant cells to extrude drugs and the circumvention of mdr is supposed to be due to the restored ability to accumulate drugs, membrane has been regarded as the crucial site for such a regulation and an important role for membrane ion exchangers has been suggested. The aim of this work was to elucidate whether the Na⁺/H⁺ antiporter is involved in the mechanism of regulation and circumvention of mdr and if 5-(N-ethyl-N-isopropyl) amiloride (EIPA), a selective inhibitor of the Na⁺/H⁺ exchanger, can modulate the functional expression of the mdr phenotype. The effect of EIPA on doxorubicin (DX) resistant cells (LoVo/DX) obtained from a human colon adenocarcinoma cell line (LoVo) was studied. EIPA at concentrations ranging from 10 to 50 μM was able to increase the antibiotic cytotoxicity in the resistant Lovo/DX cells. The reversal of DX resistance paralleled an increase of the ability of the cells to accumulate the drug. Both drug loading and sensitivity to the inhibitory effect of DX on cell proliferation were restored by EIPA in a dose-dependent way. These results suggest a new mechanism of mdr reversal and indicate that amiloride and its derivatives may be useful in reversing DX resistance and in enhancing the clinical effectiveness of chemotherapeutics.     

A proposal for the physiological significance of mdr1 and Bcrp1/Abcg2 gene expression in normal tissue regeneration and after cancer therapy

Cellular multi-drug resistance (MDR), which often develops in cancer cells of patients subjected to anti-cancer treatment, remains a significant barrier to successful cancer therapy. One of the principal causes of cellular MDR development is an increased expression of ABC-transporter genes such as mdr1 and Bcrp1/Abcg2. Despite many years of intensive research, the natural biological role of mdr1 in the context of cancer has remained elusive. Some hints about this role came, however, from an observation that P-gp, the mdr1 encoded protein, is expressed widely in stem cells and from the discovery that P-gp possesses an anti-apoptotic activity independently of exogenous drug application. Here, we discuss our own and other groups' recently published works and propose an integrated view of mdr1 and Bcrp1/Abcg2 activity during tissue regeneration in normal tissues as part of a stress-induced regeneration genetic program and in cancerous tissues in response to cancer therapy.