Multidrug resistance in chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) is characterized by the accumulation of Philadelphia chromosome-positive (Ph+) myeloid cells. Ph+ cells occur via a reciprocal translocation between the long arms of chromosomes 9 and 22 resulting in constitutively active Bcr-abl fusion protein. Tyrosine kinase inhibitors (TKIs) are used against the kinase activity of Bcr-abl fusion protein for the effective treatment of CML. However, the development of drug resistance, directed by different genetic mechanisms, is the major problem of clinical applications of TKIs. These mechanisms include mutations in the TKI binding site of Bcr-abl, overexpression of Bcr-abl, overexpression of ATP binding cassette transporters, aberrant ceramide metabolism, inhibition of apoptosis, and changes in expression levels of microRNAs. Recently, many studies have focused on understanding the molecular mechanisms of drug resistance in cancer while targeting therapies providing reversal of resistance. Cancer stem cells also have roles in tumor initiation, maintenance, progression, metastasis, and drug resistance. Uncovering the mechanisms of drug resistance can provide more efficient treatment of cancer since these findings may provide novel targets for a complete cure. In this review, we discuss recent findings on the mechanisms of multidrug resistance and its reversal in CML. © TÜBİTAK

Inorganic Nanoparticles as Drug Delivery Systems and Their Potential Role in the Treatment of Chronic Myelogenous Leukaemia

“…33 The MDR is attained through mechanisms of downregulation of the production of apoptosis-related proteins such as Bax, caspase-3, and Bcl-2, 34 drug excretion, recovery from drug-induced DNA damage, and changes in the activity of enzymes functioning in drug metabolism. 35 Nevertheless, the most important mechanism of MDR is drug excretion via permeability glycoprotein (P-gp), 36 which is a transmembrane efflux pump, encoded by Mdr1 gene functioning to decrease intracellular drug concentrations by actively transporting the drug outside the cells. 37,38 The overexpression of Mdr1 gene leads to excessive production of P-gp, increasing cell resistance to chemotherapeutic drugs; thus, increasing the chance of cancer recurrence and worsening the prognosis.…”

Organic Nanoparticles as Drug Delivery Systems and Their Potential Role in the Treatment of Chronic Myeloid Leukemia

“…12 Other mechanisms affect recovery from drug-induced DNA damage, drug excretion, and alterations in the activity of enzymes functioning in drug metabolism. 13…”

“…12 Other mechanisms affect recovery from drug-induced DNA damage, drug excretion, and alterations in the activity of enzymes functioning in drug metabolism. 13 Drug excretion via P-gp, the permeability glycoprotein, remains the most important mechanism of resistance. 14 In essence, it is an adenosine triphosphate-dependent transmembrane efflux pump encoded by the Mdr1 gene, which functions to decrease intracellular drug concentrations through active transportation of drugs out of the cells.…”

ABCB1 and BMI1 mRNA expression in patients with chronic myeloid leukemia: impact on imatinib efficacy

“…The ABCB subfamily consists of 11 genes. The first and best-characterized ABC transporter is ABCB1, which is known as the multidrug resistance (MDR1) transporter and is thought to play a role in the multidrug resistance mechanism [1415161718]. In leukemia cells, these transporters are involved in drug extrusion, while in the gut mucosa and excretory organs, particularly the kidneys and liver, they are thought to reduce the absorption and increase the elimination of drugs [1112].…”