Puzzling out iron complications in cancer drug resistance.

Iron metabolism are frequently disrupted in cancer. Patients with cancer are prone to anemia and receive transfusions frequently; the condition which results in iron overload, contributing to serious therapeutic complications. Iron is introduced as a carcinogen that may increase tumor growth. However, investigations regarding its impact on response to chemotherapy, particularly the induction of drug resistance are still limited. Here, iron contribution to cell signaling and various molecular mechanisms underlying iron-mediated drug resistance are described. A dual role of this vital element in cancer treatment is also addressed. On one hand, the need to administer iron chelators to surmount iron overload and improve the sensitivity of tumor cells to chemotherapy is discussed. On the other hand, the necessary application of iron as a therapeutic option by iron-oxide nanoparticles or ferroptosis inducers is explained. Authors hope that this paper can help unravel the clinical complications related to iron in cancer therapy.

Tetrel Bonding and Other Non-Covalent Interactions Assisted Supramolecular Aggregation in a New Pb(II) Complex of an Isonicotinohydrazide.

A new supramolecular Pb(II) complex [PbL(NO2)]n was synthesized from Pb(NO3)2, N'-(1-(pyridin-2-yl)ethylidene)isonicotinohydrazide (HL) and NaNO2. [PbL(NO2)]n is constructed from discrete [PbL(NO2)] units with an almost ideal N2O3 square pyramidal coordination environment around Pb(II). The ligand L- is coordinated through the 2-pyridyl N-atom, one aza N-atom, and the carbonyl O-atom. The nitrite ligand binds in a κ2-O,O coordination mode through both O-atoms. The Pb(II) center exhibits a hemidirected coordination geometry with a pronounced coordination gap, which allows a close approach of two additional N-atoms arising from the N=C(O) N-atom of an adjacent molecule and from the 4-pyridyl N-atom from the another adjacent molecule, yielding a N4O3 coordination, constructed from two Pb-N and three Pb-O covalent bonds, and two Pb⋯N tetrel bonds. Dimeric units in the structure of [PbL(NO2)]n are formed by the Pb⋯N=C(O) tetrel bonds and intermolecular electrostatically enforced π+⋯π- stacking interactions between the 2- and 4-pyridyl rings and further stabilized by C-H⋯π intermolecular interactions, formed by one of the methyl H-atoms and the 4-pyridyl ring. These dimers are embedded in a 2D network representing a simplified uninodal 3-connected fes (Shubnikov plane net) topology defined by the point symbol (4∙82). The Hirshfeld surface analysis of [PbL(NO2)] revealed that the intermolecular H⋯X (X = H, C, N, O) contacts occupy an overwhelming majority of the molecular surface of the [PbL(NO2)] coordination unit. Furthermore, the structure is characterized by intermolecular C⋯C and C⋯N interactions, corresponding to the intermolecular π⋯π stacking interactions. Notably, intermolecular Pb⋯N and, most interestingly, Pb⋯H interactions are remarkable contributors to the molecular surface of [PbL(NO2)]. While the former contacts are due to the Pb⋯N tetrel bonds, the latter contacts are mainly due to the interaction with the methyl H-atoms in the π⋯π stacked [PbL(NO2)] molecules. Molecular electrostatic potential (MEP) surface calculations showed marked electrostatic contributions to both the Pb⋯N tetrel bonds and the dimer forming π+⋯π- stacking interactions. Quantum theory of atoms in molecules (QTAIM) analyses underlined the tetrel bonding character of the Pb⋯N interactions. The manifold non-covalent interactions found in this supramolecular assembly are the result of the proper combination of the polyfunctional multidentate pyridine-hydrazide ligand and the small nitrito auxiliary ligand.

Iron protects childhood acute lymphoblastic leukemia cells from methotrexate cytotoxicity.

Drug resistance is a fundamental clinical concern in pediatric acute lymphoblastic leukemia (pALL), and methotrexate (MTX) is an essential chemotherapy drug administered for the treatment. In the current study, the effect of iron in response to methotrexate and its underlying mechanisms were investigated in pALL cells. CCRF-CEM and Nalm6 cell lines were selected as T and B-ALL subtypes. Cells were pretreated with ferric ammonium citrate, exposed to the IC50 concentration of MTX and cell viability was assessed using MTT, colony formation, and flow cytometry assays. Iron-loaded cells were strongly resistant to MTX cytotoxicity. The inhibitory effect of N-acetyl cysteine to reverse the acquired MTX resistance was greater than that of the iron chelator, deferasirox, highlighting the importance of iron-mediated ROS in MTX resistance. Subsequently, the upregulation of BCL2, SOD2, NRF2, and MRP1 was confirmed using quantitative RT-PCR. Moreover, a positive correlation was demonstrated between the MRP1 expression levels and bone marrow iron storage in pALL patients. Further supporting our findings were the hematoxylin and eosin-stained histological sections showing that iron-treated nude mice xenografts demonstrated significantly more liver damage than those unexposed to iron. Overall, iron is introduced as a player with a novel role contributing to methotrexate resistance in pALL. Our findings suggest that the patients' bone marrow iron stores are necessary to be assessed during the chemotherapy, and transfusions should be carefully administrated.

The relationship between iron bone marrow stores and response to treatment in pediatric acute lymphoblastic leukemia.

Iron is an intracellular element whose accumulation in the body is associated with tissue damage. This study examines the effect of iron on pediatric acute lymphoblastic leukemia (ALL) and its "response to treatment." At the end of the first year of treatment, bone marrow iron store (BMIS) was evaluated in children with ALL and the relationship between iron store and minimal residual disease was investigated. Moreover, the 3-year disease-free survival (3-DFS) of patients was determined. Patients' BMIS were compared with that of subjects with normal bone marrow. The study examined 93 children, including 78 Pre-B and 15 T-cell ALL patients. BMIS did not differ between the children with ALL and those with no evidence of cancer. BMIS was increased in 26.6% of patients at the end of the first year of treatment. Drug resistance and BM relapses were more prevalent in cases with high BMIS in both Pre-B and T-cell groups. Bone marrow iron store is not considered a risk factor for childhood ALL. However, high levels of BMIS are associated with poor response to treatment and the risk of relapse. Bone marrow iron store control during treatment can therefore help achieve better outcomes and improve the chances of recovery.

Overexpression of SORCIN is a Prognostic Biomarker for Multidrug-Resistant Pediatric Acute Lymphoblastic Leukemia and Correlates with Upregulated MDR1/P-gp.

BACKGROUND: Multidrug resistance is one of the major causes of treatment failure in pediatric acute lymphoblastic leukemia (ALL), and SORCIN is an intracellular calcium modulator protein. The current study was designed to investigate the in vitro and in vivo relationships between the expression levels of SORCIN: in tumor cell lines and children with ALL; its possible correlation with MDR1/P-glycoprotein (P-gp), a multidrug resistance-related gene; and response to therapy. MATERIALS AND METHODS: Childhood T-lymphoblastic leukemia (CCRF-CEM) cell lines resistant to methotrexate (MTX) were developed. Patient studies were performed by including 30 children with ALL at diagnosis, 3 children with bone marrow relapse, and 15 children with no symptoms of cancer. The mRNA expression profiles of SORCIN and MDR1/P-gp was assessed using quantitative polymerase chain reaction (qPCR). Minimal residual disease (MRD) was measured in the patient population, a year following the initial therapy using qPCR. RESULTS: Cell line data analyses showed a positive correlation between SORCIN mRNA levels and resistance to MTX. The difference between patient and control groups for SORCIN expression levels was not significant. However, patients with a negative response to therapy showed an increase in SORCIN mRNA levels (up to 6.8-fold) compared with those with negative MRD. In addition, the results demonstrated a significant positive correlation between SORCIN and MDR1/P-gp gene expression levels. CONCLUSION: The current study introduces, for the first time, a possible prognostic value of SORCIN in childhood ALL, which may be correlated with MDR1/P-gp gene expression in these patients.

mRNA expression profile of multidrug-resistant genes in acute lymphoblastic leukemia of children, a prognostic value for ABCA3 and ABCA2.

Multidrug resistance (MDR) is an important cause of treatment failure in acute lymphoblastic leukemia (ALL). The ABC family of membrane transporters is proposed, albeit with controversy, to be involved in this process. The present study aims to investigate the mRNA expression profile of several genes of this family, including ABCA2, ABCA3, ABCB1/MDR1, MRP1/ABCC1, MRP3/ABCC3, ABCG2/BCRP, and the intracellular transporter MVP/LRP, in childhood ALL, and to evaluate their association with response to therapy. Some genes in the present research are being studied for the first time in Iran. Using quantitative real-time PCR, we evaluated 27 children with ALL at diagnosis and 15 children with normal bone marrow. The status of response to therapy was assessed one year after the onset of therapy through investigating the IgH/TCRγ gene rearrangements. Our findings indicate a considerable and direct relationship between mRNA expression levels of ABCA2, ABCA3, MDR1, and MRP1 genes and positive minimal residual disease (MRD) measured after one year of treatment. Statistical analysis revealed that expression of these genes higher than the cutoff point will raise the risk of MRD by 15-, 6.25-, 12-, and 9-fold, respectively. No relationship was found between of MVP/LRP, MRP3 and ABCG2 genes expression and ALL prognoses. Considering the direct and significant relationship between the increased expression of ABCA2, ABCA3, MDR1, and MRP1 genes and positive risk of MRD in children with ALL, evaluating the expression profile of these genes on diagnosis may identify high risk individuals and help plan a more efficient treatment strategy.