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Discovery Medicine Jun 2023Amonafide (Amo), due to hematotoxicity and digestive tract symptoms, the clinical application of which is limited. Several studies have reported that chemotherapy side...
BACKGROUND
Amonafide (Amo), due to hematotoxicity and digestive tract symptoms, the clinical application of which is limited. Several studies have reported that chemotherapy side effects are closely related to cellular senescence accumulation. Our study aims to examine whether amonafide causes senescence in human umbilical vein endothelial cell (HUVEC) lines and investigate its mechanisms associated with senescence.
METHODS
The experiments of expression of genes and proteins associated with aging were carried out with HUVEC cell lines. The experiments were divided into a control group and an amonafide group with different days. The HUVEC senescence cells were detected by SA-β-Gal staining, Western blotting detected the protein levels of p16, p53, AMPK (Adenosine 5'-Monophosphate (AMP)-Activated Protein Kinase), mTOR (mechanistic Target of Rapamycin), p62, and LC3 (microtubule-associated protein1 light chain 3, MAP1LC3). Fluorescence detected the expression of mRFP (monomeric Red Fluorescent Protein)-GFP (Green Fluorescent Protein)-LC3 and LC3 puncta of HUVEC cells. RT-qPCR (Real-Time Quantitative Polymerase Chain Reaction) tested the expressions of , , (Interleukin), (Interleukin-6), (Interleukin-8), and (Monocyte Chemoattractant Protein-1). CCK-8 (Cell Counting Kit-8) assessed the HUVEC cell viability.
RESULTS
Here, we reported that amonafide resulted in an increased proportion of SA-β-Gal positive cells, high expression of aging-related proteins (p53 < 0.05; p16 < 0.05), and aging-related genes ( < 0.05; < 0.05; < 0.05; < 0.05; < 0.05; < 0.05) on the 3rd day. Mechanistically, amonafide could cause an increase in the levels of the mTOR ( < 0.05) on days 1 and 3, and p62 protein ( < 0.05) on day 1, and a decline in LC3II (microtubule-associated protein1 light chain 3Ⅱ)/LC3I levels ( < 0.05) on day 3, which is associated with the regulation of senescence. Additionally, the viability of HUVECs (human umbilical vein endothelial cells) was significantly inhibited by amonafide starting with a concentration of 0.8 μm ( < 0.05).
CONCLUSIONS
We first discovered that amonafide caused normal cellular senescence in our experiments. Amonafide-induced cellular aging by inhibiting autophagy and activating the mTOR pathway. The findings may offer new strategies for managing adverse reactions to amonafide.
Topics: Humans; Human Umbilical Vein Endothelial Cells; Interleukin-8; Tumor Suppressor Protein p53; Interleukin-6; TOR Serine-Threonine Kinases; Autophagy; Cellular Senescence
PubMed: 37272093
DOI: 10.24976/Discov.Med.202335176.27 -
Expert Opinion on Investigational Drugs Jul 2011Amonafide is a novel topoisomerase II (Topo II) inhibitor and DNA intercalator that induces apoptotic signaling by blocking the binding of Topo II to DNA. Amonafide... (Review)
Review
INTRODUCTION
Amonafide is a novel topoisomerase II (Topo II) inhibitor and DNA intercalator that induces apoptotic signaling by blocking the binding of Topo II to DNA. Amonafide retains cytotoxic activity even in the presence of P-glycoprotein (Pgp)-mediated multi-drug resistance (MDR), a major contributor to clinical treatment failure.
AREAS COVERED
In vitro, Pgp-mediated transport (efflux) of amonafide from myeloblasts obtained from patients with secondary acute myeloid leukemia (sAML) was significantly less than efflux of daunorubicin. Amonafide has shown efficacy in patients with sAML, as well as in patients with poor prognostic characteristics such as older age and unfavorable cytogenetics, all associated with MDR. Improved antileukemic activity is observed when amonafide is given together with cytarabine, rather than as monotherapy, with a complete remission rate of ∼ 40% in a recent Phase II trial in sAML. The efficacy of amonafide was maintained among poor-risk subsets of patients, including older patients and patients who had previous myelodysplastic syndrome or previous leukemogenic therapy. The safety profile was acceptable and manageable.
EXPERT OPINION
Amonafide plus cytarabine may have clinical utility in patients with sAML and in other poor-risk subgroups of acute myeloid leukemia (AML). Ongoing trials will help define the role for amonafide in the treatment of poor-risk AML.
Topics: Adenine; Animals; Antineoplastic Agents; Clinical Trials as Topic; DNA Topoisomerases, Type II; Drug Resistance, Neoplasm; Enzyme Inhibitors; Humans; Leukemia, Myeloid, Acute; Naphthalimides; Organophosphonates; Survival Rate; Treatment Outcome
PubMed: 21591994
DOI: 10.1517/13543784.2011.585756 -
Expert Review of Hematology Feb 2012Development of the novel topoisomerase II inhibitor, amonafide, began almost 40 years ago. The drug was selected for further investigation owing to evidence of marked... (Review)
Review
Development of the novel topoisomerase II inhibitor, amonafide, began almost 40 years ago. The drug was selected for further investigation owing to evidence of marked antineoplastic efficacy in preclinical models of cancer. When its usefulness in the treatment of various solid malignancies proved limited, focus was shifted to establishing its use as an antileukemic agent, specifically against secondary and treatment-associated acute myeloid leukemia (AML). While Phase I and II studies gave rise to hopes that amonafide might hold the key to treating older patients, including those with multidrug resistant, cytogenetically unfavorable secondary and treatment-associated AML, when used in combination with cytarabine, it failed to demonstrate a survival advantage over standard-of-care therapy in randomized studies. This article will outline the development of amonafide from the laboratory to the bedside and discuss the potential place that this agent has in the current management of AML.
Topics: Adenine; Antineoplastic Agents; Clinical Trials as Topic; Female; Humans; Leukemia, Myeloid, Acute; Male; Naphthalimides; Organophosphonates; Topoisomerase II Inhibitors
PubMed: 22272701
DOI: 10.1586/ehm.11.68 -
Cancer Management and Research 2019Human melanoma is a malignant tumor originated from melanocytes with high invasion, metastasis, and poor prognosis. In this study, the effects of naphthalimides UNBS5162...
BACKGROUND
Human melanoma is a malignant tumor originated from melanocytes with high invasion, metastasis, and poor prognosis. In this study, the effects of naphthalimides UNBS5162 and amonafide on the properties of proliferation and apoptosis in human melanoma cells were confirmed.
METHODS
Cell proliferation was determined by CCK8 and clone formation assay. Transwell assay was performed to detect the migration and invasion of M14 and A375 cells. Cell apoptosis was estimated using flow cytometry.
RESULTS
In a drug sensitivity assay, cell viability decreased with increasing concentrations of UNBS5162 or amonafide. Likewise, proliferation of M14 or A375 cells treated with 10 μM UNBS5162 or 8 μM amonafide decreased significantly when compared with negative control (NC) cells, their inhibition effect verified by means of a clone formation assay. After the treatment with UNBS5162 or amonafide, the migration of melanoma cells was inhibited in a dosede-pendent manner. The number of invaded cells treated with UNBS5162 was also significantly reduced when compared with those of the NC cells. The apoptotic cell numbers treated with UNBS5162 or amonafide decreased significantly when compared with the M14 and A375 cells in the NC group. According to Western blot results, phosphorylation of AKT and expressions of mesenchymal marker factors were inhibited in cells treated with UNBS5162 or amonafide.
CONCLUSION
These results reveal that UNBS5162 inhibits the cell activity of melanoma cells through the AKT/mTOR signaling pathway, and reverses epithelial-mesenchymal transition conversion in human melanoma cells. This study on UNBS5162 and amonafide in melanomas provides an experimental basis of their uses and potential value on human melanoma treatment.
PubMed: 30962721
DOI: 10.2147/CMAR.S177623 -
European Journal of Cancer (Oxford,... 1990
Topics: Adenine; Aged; Antineoplastic Agents; Colorectal Neoplasms; Female; Humans; Imides; Isoquinolines; Male; Middle Aged; Naphthalimides; Neoplasm Metastasis; Organophosphonates
PubMed: 2145944
DOI: 10.1016/0277-5379(90)90207-a -
Cancer Chemotherapy and Pharmacology 1988Amonafide, one of a series of imide derivatives of 1,8-naphthalic acid synthesized by Brana et al. has shown significant antitumor activity against a variety of...
Amonafide, one of a series of imide derivatives of 1,8-naphthalic acid synthesized by Brana et al. has shown significant antitumor activity against a variety of experimental tumors, including L1210 leukemia and P388 leukemia. Along with the clinical trial at our institute, we have studied the disposition of Amonafide in dogs by HPLC and fluorometry. Six dogs received Amonafide i.v. at 5 mg/kg (100 mg/m2) over 15 min; three were sacrificed at 6 h, and three at 24 h. The initial plasma t1/2 of Amonafide was 2.4 +/- 0.4 min, the intermediate t1/2, 26.8 +/- 3.7 min, and the terminal t1/2, 21.7 +/- 4.0 h. The peak plasma concentration achieved was 6.3 +/- 1.7 micrograms/ml. The average apparent volume of distribution was 12.84 +/- 0.54 1/kg, and the total clearance was 0.56 +/- 0.16 1/kg/h. In 24 h, 9.5% +/- 0.2% of the administered dose was excreted in the urine as the parent drug, and 7.4% +/- 1.4% in the bile in 6 h. Amonafide penetrated the CSF readily and achieved the highest concentration 20-25 min after administration, which was 30% of the concurrent plasma level. Amonafide underwent extensive metabolism to at least three major metabolites and two or more minor metabolites. The alpha and beta plasma t1/2 of the major metabolite, an N-oxide derivative, were 24.8 min and 28.6 h, respectively. The 24-h cumulative urinary excretion was 1.4% of the injected dose, and the cumulative biliary excretion was 16.7% in 6 h. At autopsy 6 h after dosing, the liver contained the highest percentage (0.23% of administered dose) of unchanged Amonafide, followed by the stomach (0.11%), lung (0.04%), kidney (0.04%), and pancreas (0.03%). The rest of the major organs retained less than 0.02% of the Amonafide dose. One day after dosing, no detectable amount of Amonafide was found in any of these tissues, indicating that Amonafide appears to be extensively metabolized and not significantly retained in the dog.
Topics: Adenine; Animals; Antineoplastic Agents; Chemical Phenomena; Chemistry; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Dogs; Female; Fluorometry; Gas Chromatography-Mass Spectrometry; Imides; Infusions, Intravenous; Isoquinolines; Male; Naphthalimides; Organophosphonates; Oxidation-Reduction; Regression Analysis; Software; Tissue Distribution
PubMed: 3349561
DOI: 10.1007/BF00257359 -
Leukemia Research Mar 2008Over-expression of P-glycoprotein (Pgp+) has been related to resistance to classical Topo II inhibitors used in the treatment of AML and is common in patients with...
Over-expression of P-glycoprotein (Pgp+) has been related to resistance to classical Topo II inhibitors used in the treatment of AML and is common in patients with poor-prognosis, such as those with secondary AML (sAML). Since clinical trials with amonafide, a unique ATP-independent Topo II inhibitor, in combination with cytarabine, have shown significant efficacy for remission induction in patients with sAML, we compared the cytotoxic effect of amonafide (amonafide l-malate, Xanafide) to the classical Topo II inhibitors (daunorubicin, doxorubicin, idarubicin, etoposide, and mitoxantrone) in K562 leukemia cells and in the MDR subline, K562/DOX. Pgp expression was found to be approximately 6.5-fold greater in K562/DOX and causes the rapid efflux of these drugs from the leukemia cell. As a consequence, the LC(50) values for the classical Topo II inhibitor drugs tested were each increased up to 3 log units. A similar result was also observed in murine P388 and P388/ADR leukemia cells. Addition of cyclosporin A reversed K562/DOX resistance for the classical Topo II inhibitors, decreasing their LC(50) values to the levels observed with wild type cells but had no effect on amonafide potency in Pgp+ or wild type cells. Further examination of amonafide in bidirectional Caco-2 and MDR1-MDCK models confirmed that amonafide is neither a substrate nor inhibitor of Pgp. These observations suggest that amonafide is a promising therapeutic candidate directed toward bypassing this common mechanism of drug resistance encountered in the treatment of patients with AML, and possibly in other resistant hematological malignancies as well.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Adenine; Animals; Cell Line, Tumor; Drug Resistance, Multiple; Enzyme Inhibitors; Humans; Imides; Isoquinolines; Mice; Naphthalimides; Organophosphonates; Topoisomerase II Inhibitors
PubMed: 17826829
DOI: 10.1016/j.leukres.2007.07.017 -
Bioorganic Chemistry Dec 2019Novel water-soluble 4-aminonaphthalimides were synthesised and their cellular fluorescent imaging, cytotoxicity and ability to induced apoptosis evaluated. The lead...
Novel water-soluble 4-aminonaphthalimides were synthesised and their cellular fluorescent imaging, cytotoxicity and ability to induced apoptosis evaluated. The lead compound 1 was designed from the cross-fertilisation of the basic hydrophilic amino pharmacophore of mitoxantrone, and an aminonaphthalimide scaffold of the drug candidate, amonafide. The compounds are also fluorescent pH probes based on photoinduced electron transfer (PET) and internal charge transfer (ICT). The compounds are sensitive to solvent polarity with large Stoke shifts (>90 nm) and provide emissive-coloured solutions (blue to yellow). Excited state pKs of 9.0-9.3 and fluorescence quantum yields of 0.47-0.58 were determined in water. The cytotoxicity and cellular fluorescent imaging properties of the compounds were tested on human cancer cell lines K562 and MCF-7 by the MTT assay, phase contrast and fluorescence microscopy. Compounds 1 and 3 with flexible aminoalkyl chains exhibited GI comparable to amonafide, while 2 and 4 with a rigid piperazine moiety and butyl chain are less cytotoxic. Fluorescence microscopy with 1 allowed for the visualization of the intracellular microenvironment exemplifying the potential utility of such hybrid molecules as anticancer and fluorescent cellular imaging agents.
Topics: Adenine; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Fluorescent Dyes; Humans; Microscopy, Fluorescence; Mitoxantrone; Naphthalimides; Organophosphonates; Phthalimides; Spectrometry, Fluorescence
PubMed: 31561011
DOI: 10.1016/j.bioorg.2019.103287 -
Clinical Cancer Research : An Official... Jul 1995Amonafide is a new imide derivative of naphthalic acid. The drug had demonstrated significant activity in preclinical studies and some activity in Phase I trials. The... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Amonafide is a new imide derivative of naphthalic acid. The drug had demonstrated significant activity in preclinical studies and some activity in Phase I trials. The drug is extensively metabolized and detected in plasma and urine. Its toxicity has previously been correlated to the formation of an active metabolite, N-acetyl-amonafide. Amonafide was chosen for inclusion in the Cancer and Leukemia Group B (CALGB) master metastatic breast cancer protocol. CALGB 8642 randomizes previously untreated metastatic breast cancer patients either to one of several Phase II agents given for up to four cycles and then followed by standard cyclophosphamide-doxorubicin-5-fluorouracil, or to immediate treatment with standard cyclophosphamide-doxorubicin-5-fluorouracil. The end point of CALGB 8642 is to assess the difference in survival, toxicity, and overall response when limited exposure to Phase II agents precedes standard chemotherapy. This report deals only with amonafide as a Phase II agent. Comparisons with the cyclophosphamide-doxorubicin-5-fluorouracil arm will not be addressed. Patients had to have histologically documented measurable breast cancer and a performance status of 0-1. Patients could not have had prior chemotherapy for metastatic disease. Prior adjuvant chemotherapy was permitted. Patients could not have visceral crisis. Amonafide was given at 300 mg/m2/day i.v. for 5 days, and repeated at 21-day intervals for a maximum of four cycles. Escalation and reduction in dose was mandated dependent on hematotoxicity or lack thereof. Toxicity was primarily hematological and bimodal: 32% had grade 3 or 4 leukopenia and 24% had grade 3 or 4 thrombocytopenia; 22% had no leukopenia and 44% had no thrombocytopenia. The response rate was 18%, including one complete response. When response was analyzed by hematological toxicity, there was a 35.7% response if patients had leukopenia grade 3/4 (versus 8.3%, P = 0.08). There was a 50% response if patients had thrombocytopenia grade 3/4 (versus 7.1%, P = <0.01). We conclude that amonafide is somewhat active in previously untreated breast cancer patients. There may be a steep dose-response curve, based on the significant correlation between myelosuppression and response. Rates of responses in patients adequately dosed (i.e., with significant hematotoxicity) with amonafide ranged from 35 to 50%. Further studies will incorporate individualized dosing based on pretreatment acetylator phenotyping.
Topics: Adenine; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Female; Fluorouracil; Humans; Imides; Isoquinolines; Menopause; Middle Aged; Naphthalimides; Neoplasm Metastasis; Organophosphonates; Receptors, Estrogen
PubMed: 9816035
DOI: No ID Found -
Chemical Biology & Drug Design May 2017With the aim of upregulating antitumor efficacy and downregulating adverse effects, the amino group in the three-position of amonafide aromatic ring was modified by...
With the aim of upregulating antitumor efficacy and downregulating adverse effects, the amino group in the three-position of amonafide aromatic ring was modified by coupling with different amine/polyamine motifs via two linkers. Two series of naphthalimide derivatives were designed and synthesized and evaluated for their antitumor properties in vitro and in vivo. The preliminary in vitro trials revealed that compounds with urea as the linker were not active, and the presence of aspirin elevated the potency of 6k against tumor cells, wound healing, and the protein expression of cyclic D1 and MMP9. The in vivo trials on three H22 tumor transplant models demonstrated that the combination of 6k and aspirin markedly improved the efficacy in terms of inhibitive effect, pulmonary metastasis, and extension of the life span. More importantly, the combination of 6k and aspirin displayed the reduced side-effects compared to that of amonafide.
Topics: Adenine; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Microscopy, Fluorescence; Naphthalimides; Neoplasms; Organophosphonates; Polyamines; Transplantation, Heterologous
PubMed: 27762101
DOI: 10.1111/cbdd.12888