Daunorubicin

Daunorubicin is an inhibitor of DNA topoisomerase II [1].

Daunorubicin is an anthracycline antibiotic. It is also used as an effective chemotherapeutic agent against tumors especially acute myeloid leukaemia and acute lymphocytic leukaemia. Daunorubicin can affect the metabolism and synthesis of DNA and RNA. In the in vitro assay, daunorubicin inhibits the incorporation of thymidine and uridine into L1210 cells. It also inhibits the incorporation of labeled precursors into the isolated DNA and RNA from incubated cells. When treated with leukemic cells isolated from acute lymphocytic leukemia patients, daunorubicin significantly inhibits the biosynthesis of the DNA and RNA macromolecules [2, 3].

References:
[1] Hande K R. Etoposide: four decades of development of a topoisomerase II inhibitor. European Journal of Cancer, 1998, 34(10): 1514-1521.
[2] Momparler R L, Karon M, Siegel S E, et al. Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells. Cancer Research, 1976, 36(8): 2891-2895.
[3] Meriwether W D, Bachur N R. Inhibition of DNA and RNA metabolism by daunorubicin and adriamycin in L1210 mouse leukemia. Cancer research, 1972, 32(6): 1137-1142.

The efficacy of WGA modified daunorubicin anti-resistant liposomes in treatment of drug-resistant MCF-7 breast cancer.[Pubmed:28277825]

J Drug Target. 2017 Jul;25(6):541-553.

BACKGROUND: Breast cancer is the most common malignancy and remains a leading cause of cancer-related deaths in female. Chemotherapy failure of breast cancer is mainly associated with multidrug resistance of cancer cells. PURPOSE: The WGA modified Daunorubicin anti-resistant liposomes were developed for circumventing the multidrug resistance and eliminating cancer cells. METHODS: WGA was modified on liposomal surface for increasing the intracellular uptake. Tetrandrine was inserted into the phospholipid bilayer for reversing cancer drug-resistance, and Daunorubicin was encapsulated in liposomal aqueous core as an anticancer agent. Evaluations were performed on MCF-7 cells, MCF-7/ADR cells and xenografts of MCF-7/ADR cells. RESULTS: In vitro results showed that WGA modified Daunorubicin anti-resistant liposomes exhibited suitable physicochemical properties, significantly increased intracellular uptake in both MCF-7 cells and MCF-7/ADR cells, and circumvented the multidrug resistance via inhibiting P-gp. In vivo results demonstrated that the targeting liposomes showed a long-circulatory effect in blood system, and could remarkably accumulate at the tumor location. The involved action mechanisms for the enhanced anticancer efficacy were activation of pro-apoptotic proteins (Bax and Bok), apoptotic enzymes (caspase 8, caspase 9 and caspase 3). CONCLUSION: The established WGA modified Daunorubicin anti-resistant liposomes could provide a potential strategy for treating resistant MCF-7 breast cancer.

The daunorubicin interplay with mimetic model membranes of cancer cells: A biophysical interpretation.[Pubmed:28153496]

Biochim Biophys Acta Biomembr. 2017 May;1859(5):941-948.

The present work aimed to study the interactions between the anticancer drug Daunorubicin and lipid membrane mimetic models of cancer cells composed by their most representative classes of phospholipids, with different degrees of complexity. Regarding these anticancer drug-membrane interactions, several biophysical parameters were assessed using liposomes (LUVs) composed of different molar ratios of DMPC, DOPC, DPPS, DOPE and Chol. In this context, Daunorubicin's membrane concentration was determined by calculating its partition coefficient (Kp) between liposomes and water using derivative UV/vis spectrophotometry at 37 degrees C and pH6.3, a typical tumoral microenvironment. Characterization of the zeta potential of such model membranes, in both the absence and presence of the compound, was accomplished through Electrophoretic Light Scattering (ELS). Fluorescence quenching studies, which determine the location of the drug within the bilayer, were carried out using liposomes labelled with DPH and TMA-DPH, fluorescent probes with known membrane position. Temperature dependent steady-state anisotropy assays were also performed to measure the Daunorubicin effect on the membranes' microviscosity. The overall results support that Daunorubicin permeation depends on the phospholipid membrane composition and causes alterations in the biophysical properties of the bilayers, namely in the membrane fluidity. The interaction of Daunorubicin with the studied phospholipids is mainly driven by electrostatic and hydrophobic interactions. These insights demonstrated that not only membranes can affect Daunorubicin accumulation in cells but the compound can alter the properties of membranes. The changes produced by Daunorubicin on the lipid structure may constitute an additional mechanism of action, which might lead to modifications in the location and, consequently, the activity of membrane signaling proteins.

What Is the Best Daunorubicin Dose and Schedule for Acute Myeloid Leukemia Induction?[Pubmed:28154969]

Curr Treat Options Oncol. 2017 Jan;18(1):3.

OPINION STATEMENT: Daunorubicin dose intensification for induction in acute myeloid leukemia has been reported as an effective strategy in recent trials to improve patient outcomes without worsening treatment-related toxicity. Based on available evidence, 90 mg/m(2) of Daunorubicin given for three consecutive days (cumulative dose 270 mg/m(2)) as a part of the "7 + 3" induction regimen along with cytarabine is the most effective dose to achieve a complete remission as well as improve survival in patients who can tolerate it. This should be considered strongly in younger patients (less than 65 years of age and especially in those less than 50 years) irrespective of cytogenetic risk (likely more beneficial for favorable and intermediate risk) or molecular mutations (definitely in those with NPM1 or FLT3-ITD mutations). Among older acute myeloid leukemia (AML) patients (>65 years), using a higher dose of Daunorubicin may not improve survival. It is unclear if Daunorubicin at 60 mg/m(2) for 3 days is as efficacious as the 90 mg/m(2) dose but may be used when there are concerns about tolerability of the higher dose. Although 90 mg/m(2) has no more adverse effects compared to 45 mg/m(2) of Daunorubicin, increasing dosage beyond a cumulative dose of 330 mg/m(2) is detrimental due to increase in early mortality. Idarubicin 12 mg/m(2) for 3 days is an alternative with the possibility of better long-term outcomes. Elderly patients with AML and those with unfavorable cytogenetics, secondary, or treatment-related disease remain challenging to treat. All patients should be treated on clinical trials when available.

Downregulation of myogenic microRNAs in sub-chronic but not in sub-acute model of daunorubicin-induced cardiomyopathy.[Pubmed:28303410]

Mol Cell Biochem. 2017 Aug;432(1-2):79-89.

Cardiac muscle-related microRNAs play important roles in cardiac development and disease by translational silencing of mRNAs, the dominant mechanism of microRNA action. To test whether they could be involved in Daunorubicin-associated cardiomyopathy (DACM), we determined expression patterns of myomiRs in two distinct models of DACM. We used 10-12 weeks old male Wistar rats. In the sub-acute model, rats were administered with six doses of Daunorubicin (DAU-A, 3 mg/kg, i.p., every 48 h). Rats were sacrificed two days after the last dose. In the sub-chronic model, anaesthetized rats were administered a single dose of Daunorubicin (15 mg/kg, i.v., DAU-C). Age-matched controls (CON) received vehicle. Rats were sacrificed eight weeks later. Left ventricular (LV) functions (LV pressure, rate of pressure development, +dP/dt and decline, -dP/dt) were measured using left ventricular catheterization. Expressions of myomiRs (miR-208a, miR-499, miR-1 and miR-133a), markers of cardiac failure (atrial and brain natriuretic peptides genes; Nppa and Nppb) and myosin heavy chain genes (Myh6, Myh7, Myh7b) in cardiac tissue were determined by RT-PCR. Protein expression of gp91phox NADPH oxidase subunit was detected by immunoblotting. Both DAU groups exhibited a similar depression of LV function, and LV weight reduction, accompanied by an upregulation of natriuretic peptides, and a decrease of Myh6 to total Myh ratio (-18% in DAU-A and - 25% in DAU-C, as compared to controls; both P < 0.05). DAU-C, but not DAU-A rats had a 35% mortality rate and exhibited a significantly increased gp91phox expression (DAU-C: 197 +/- 33 versus CON-C: 100 +/- 11; P < 0.05). Interestingly, myomiRs levels were only reduced in DAU-C compared to CON-C (miR-208: -45%, miR-499: -30%, miR-1: -29%, miR- and miR133a: -25%; all P < 0.05) but were unaltered in DAU-A. The lack of myomiRs expression, particularly in sub-chronic model, suggests the loss of control of myomiRs network on late progression of DACM. We suppose that the poor inhibition of mRNA targets might contribute to chronic DACM.

Daunorubicin (Daunomycin; RP 13057; Rubidomycin) is a topoisomerase II inhibitor with potent antineoplastic activities. Daunorubicin (Daunomycin; RP 13057; Rubidomycin) inhibites DNA and RNA synthesis in sensitive and resistant Ehrlich ascites tumor cells.

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