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Current Medicinal Chemistry 2016In the late 1980s, reports emerged describing experimental antibacterial quinolones having significant potency against eukaryotic Type II topoisomerases (topo II) and... (Review)
Review
In the late 1980s, reports emerged describing experimental antibacterial quinolones having significant potency against eukaryotic Type II topoisomerases (topo II) and showing cytotoxic activity against tumor cell lines. As a result, several pharmaceutical companies initiated quinolone anticancer programs to explore the potential of this class in comparison to conventional human topo II inhibiting antitumor drugs such as doxorubicin and etoposide. In this review, we present a modern re-evaluation of the anticancer potential of the quinolone class in the context of today's predominantly pathway-based (rather than cytotoxicity-based) oncology drug R&D environment. The quinolone eukaryotic SAR is comprehensively discussed, contrasted with the corresponding prokaryotic data, and merged with recent structural biology information which is now beginning to help explain the basis for that SAR. Quinolone topo II inhibitors appear to be much less susceptible to efflux-mediated resistance, a current limitation of therapy with conventional agents. Recent advances in the biological understanding of human topo II isoforms suggest that significant progress might now be made in overcoming two other treatment-limiting disadvantages of conventional topo II inhibitors, namely cardiotoxicity and drug-induced secondary leukemias. We propose that quinolone class topo II inhibitors could have a useful future therapeutic role due to the continued need for effective topo II drugs in many cancer treatment settings, and due to the recent biological and structural advances which can now provide, for the first time, specific guidance for the design of a new class of inhibitors potentially superior to existing agents.
Topics: Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; DNA Topoisomerases, Type II; Drug Discovery; Humans; Models, Molecular; Neoplasms; Quinolones; Signal Transduction; Topoisomerase II Inhibitors
PubMed: 26695512
DOI: 10.2174/0929867323666151223095839 -
European Journal of Pharmacology Nov 2020Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil (MMF), an immunosuppressive drug approved for the prophylaxis of allograft rejection in... (Review)
Review
Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil (MMF), an immunosuppressive drug approved for the prophylaxis of allograft rejection in transplant recipients. Recent advances in the role of the type II isoform of inosine-5'-monophosphate dehydrogenase (IMPDH2) in the tumorigenesis of various types of cancer have called for a second look of MPA, the first IMPDH2 inhibitor discovered a hundred years ago, to be repurposed as an anticancer agent. Over a half century, a number of in vitro and in vivo experiments have consistently shown anticancer activity of MPA against several cell lines obtained from different malignancies and murine models. However, a few clinical trials have been conducted to investigate its anticancer activity in humans, and most of which have shown unsatisfactory results. Understanding of available evidence and underlying mechanism of action is a key step to be done so as to facilitate further investigations of MPA to reach its full therapeutic potential as an anticancer agent. This article provides a comprehensive review of non-clinical and clinical evidence available to date, with the emphasis on the molecular mechanism of action in which MPA exerts its anticancer activities: induction of apoptosis, induction of cell cycle arrest, and alteration of tumor microenvironment. Future perspective for further development of MPA to be an anticancer agent is extensively discussed, with the aim of translating the anticancer property of MPA from bench to bedside.
Topics: Animals; Antibiotics, Antineoplastic; Humans; IMP Dehydrogenase; Mycophenolic Acid; Neoplasms
PubMed: 32949604
DOI: 10.1016/j.ejphar.2020.173580 -
Life Sciences May 2018Doxorubicin (Dox) is a valuable anticancer drug for hematologic and solid tumors. Yet, it can cause multi-organ toxicities in various patients. Since toxicity evaluation... (Review)
Review
Doxorubicin (Dox) is a valuable anticancer drug for hematologic and solid tumors. Yet, it can cause multi-organ toxicities in various patients. Since toxicity evaluation is a major criterion to discuss for every experiment, the current mini-review focuses on the toxicity of Dox to multiple organs and suggests the most probable mechanism. Though several mechanisms have been suggested, the role of oxidative stress remains elusive among other mechanisms and remains the most probable mechanism for cardiotoxic effect of Dox.
Topics: Animals; Antibiotics, Antineoplastic; Cardiotoxicity; Doxorubicin; Hematologic Neoplasms; Humans; Organ Specificity; Oxidative Stress
PubMed: 29534993
DOI: 10.1016/j.lfs.2018.03.023 -
Advanced Drug Delivery Reviews Nov 2021We review the drug development of lyso-thermosensitive liposomal doxorubicin (LTLD) which is the first heat-activated formulation of a liposomal drug carrier to be... (Review)
Review
We review the drug development of lyso-thermosensitive liposomal doxorubicin (LTLD) which is the first heat-activated formulation of a liposomal drug carrier to be utilized in human clinical trials. This class of compounds is designed to carry a payload of a cytotoxic agent and adequately circulate in order to accumulate at a tumor that is being heated. At the target the carrier is activated by heat and releases its contents at high concentrations. We summarize the preclinical and clinical experience of LTLD including its successes and challenges in the development process.
Topics: Animals; Antibiotics, Antineoplastic; Doxorubicin; Drug Delivery Systems; Drug Development; Drug Liberation; Humans; Hyperthermia; Hyperthermia, Induced; Polyethylene Glycols
PubMed: 34555486
DOI: 10.1016/j.addr.2021.113985 -
Journal of Drug Targeting Apr 2018Doxorubicin (DOX), as an anthracycline, plays an important role in chemotherapy. But multidrug resistance (MDR) tremendously retards the anticancer effect of DOX and... (Review)
Review
Doxorubicin (DOX), as an anthracycline, plays an important role in chemotherapy. But multidrug resistance (MDR) tremendously retards the anticancer effect of DOX and results in the failure of chemotherapy. Multifunctional micelles emerge as a valid strategy to load DOX by physical encapsulation or chemical binding to be delivered to cancer cells against MDR. In this review, mechanism of MDR of DOX is simply described. Multifunctional co-delivery micelles of DOX and main MDR modulators have been summarised in detail. DOX-loaded multifunctional polymeric micelles are also introduced to alleviate MDR of DOX, in which polymers act as MDR modulators.
Topics: Antibiotics, Antineoplastic; Doxorubicin; Drug Carriers; Drug Delivery Systems; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Micelles; Neoplasms; Polymers
PubMed: 28901798
DOI: 10.1080/1061186X.2017.1379525 -
Apoptosis : An International Journal on... Jun 2024Doxorubicin (DOX) is an anthracycline antibiotic used as an antitumor treatment. However, its clinical application is limited due to severe side effects such as...
Doxorubicin (DOX) is an anthracycline antibiotic used as an antitumor treatment. However, its clinical application is limited due to severe side effects such as cardiotoxicity. In recent years, numerous studies have demonstrated that cellular aging has become a therapeutic target for DOX-induced cardiomyopathy. However, the underlying mechanism and specific molecular targets of DOX-induced cardiomyocyte aging remain unclear. Poly (ADP-ribose) polymerase (PARP) is a family of protein post-translational modification enzymes in eukaryotic cells, including 18 members. PARP-1, the most well-studied member of this family, has become a potential molecular target for the prevention and treatment of various cardiovascular diseases, such as DOX cardiomyopathy and heart failure. PARP-1 and PARP-2 share 69% homology in the catalytic regions. However, they do not entirely overlap in function. The role of PARP-2 in cardiovascular diseases, especially in DOX-induced cardiomyocyte aging, is less studied. In this study, we found for the first time that down-regulation of PARP-2 can inhibit DOX-induced cellular aging in cardiomyocytes. On the contrary, overexpression of PARP-2 can aggravate DOX-induced cardiomyocyte aging and injury. Further research showed that PARP-2 inhibited the expression and activity of SIRT1, which in turn was involved in the development of DOX-induced cardiomyocyte aging and injury. Our findings provide a preliminary experimental basis for establishing PARP-2 as a new target for preventing and treating DOX cardiomyopathy and related drug development.
Topics: Doxorubicin; Myocytes, Cardiac; Sirtuin 1; Animals; Cellular Senescence; Poly(ADP-ribose) Polymerases; Rats; Cardiotoxicity; Apoptosis; Rats, Sprague-Dawley; Antibiotics, Antineoplastic; Cardiomyopathies; Humans
PubMed: 38281279
DOI: 10.1007/s10495-023-01929-y -
Antioxidants & Redox Signaling May 2018Chemotherapy is currently the principal method for treating many malignancies. Thus, the development of improved antitumor drugs with enhanced efficacy and selectivity... (Review)
Review
SIGNIFICANCE
Chemotherapy is currently the principal method for treating many malignancies. Thus, the development of improved antitumor drugs with enhanced efficacy and selectivity remains a high priority. Recent Advances: Anthracycline antibiotics (AAs), for example, doxorubicin, daunomycin, and mitomycin C, belong to an important family of antitumor agents widely used in chemotherapy. These compounds are all quinones. They are, thus, capable of being reduced by appropriate chemicals or reductases. One of their important properties is that under aerobic conditions their reduced forms undergo oxidation, with concomitant generation of reactive oxygen species (ROS), namely, superoxide anion radicals, hydrogen peroxide, and hydroxyl radicals. The presence of metal ions is essential for the generation of ROS by AAs in biological systems.
CRITICAL ISSUES
A fundamental shortcoming of the AAs is their high cardiotoxicity. We have proposed, and experimentally realized, a new type of quinones that is capable of coordinating metal ions. We have demonstrated in vitro that they can be reduced by electron transfer chains and glutathione with concomitant generation of ROS. They can also produce ROS under photo-excitation. The mechanisms of these reactions have been characterized by using nuclear magnetic resonance and electron paramagnetic resonance.
FUTURE DIRECTIONS
To enhance their therapeutic effectiveness, and decrease cardiotoxicity and other side effects, we intend to conjugate the quinone chelators with monoclonal antibodies and peptide hormones that are specifically targeted to receptors on the cancer cell surface. Some such candidates have already been synthesized. An alternative approach for delivery of our compounds involves the use of specific peptide-based nanoparticles. In addition, our novel approach for treating malignancies is also suitable for photodynamic therapy. Antioxid. Redox Signal. 28, 1394-1403.
Topics: Antibiotics, Antineoplastic; Benzoquinones; Electron Spin Resonance Spectroscopy; Humans; Neoplasms; Oxidation-Reduction; Reactive Oxygen Species
PubMed: 29161882
DOI: 10.1089/ars.2017.7406 -
Journal of Inorganic Biochemistry Mar 2016The antineoplastic and antibiotic natural product mithramycin (MTM) is used against cancer-related hypercalcemia and, experimentally, against Ewing sarcoma and lung...
The antineoplastic and antibiotic natural product mithramycin (MTM) is used against cancer-related hypercalcemia and, experimentally, against Ewing sarcoma and lung cancers. MTM exerts its cytotoxic effect by binding DNA as a divalent metal ion (Me(2+))-coordinated dimer and disrupting the function of transcription factors. A precise molecular mechanism of action of MTM, needed to develop MTM analogues selective against desired transcription factors, is lacking. Although it is known that MTM binds G/C-rich DNA, the exact DNA recognition rules that would allow one to map MTM binding sites remain incompletely understood. Towards this goal, we quantitatively investigated dimerization of MTM and several of its analogues, MTM SDK (for Short side chain, DiKeto), MTM SA-Trp (for Short side chain and Acid), MTM SA-Ala, and a biosynthetic precursor premithramycin B (PreMTM B), and measured the binding affinities of these molecules to DNA oligomers of different sequences and structural forms at physiological salt concentrations. We show that MTM and its analogues form stable dimers even in the absence of DNA. All molecules, except for PreMTM B, can bind DNA with the following rank order of affinities (strong to weak): MTM=MTM SDK>MTM SA-Trp>MTM SA-Ala. An X(G/C)(G/C)X motif, where X is any base, is necessary and sufficient for MTM binding to DNA, without a strong dependence on DNA conformation. These recognition rules will aid in mapping MTM sites across different promoters towards development of MTM analogues as useful anticancer agents.
Topics: Antibiotics, Antineoplastic; DNA; Dimerization; Plicamycin
PubMed: 26760230
DOI: 10.1016/j.jinorgbio.2015.12.011 -
The Journal of Knee Surgery Feb 2020As the number of total joint arthroplasties continues to rise, periprosthetic joint infection (PJI), a significant and devastating complication of total joint... (Review)
Review
As the number of total joint arthroplasties continues to rise, periprosthetic joint infection (PJI), a significant and devastating complication of total joint arthroplasty, may also increase. In PJI, bacterial biofilms are formed by causative pathogens surrounded by extracellular matrix with relatively dormant cells that can persist, resulting in a barrier against the host immune system and antibiotics. These biofilms not only contribute to the pathogenesis of PJI but also result in diagnostic challenges, antibiotic resistance, and PJI treatment failure. This review discusses the development of biofilms and key features associated with biofilm pathogenicity in PJI, current PJI diagnostic methods and their limitations, and current treatment options. Additionally, this article explores novel approaches to treat PJI, including targeting persister bacteria, immunotherapy, antimicrobial peptides, nanoparticles, and bacteriophage therapy. Biofilm eradication can also be achieved through enzymatic therapy, photodynamic therapy, and ultrasound. Finally, this review discusses novel techniques to prevent PJI, including improved irrigation solutions, smart implants with antimicrobial properties, inhibition of quorum sensing, and vaccines, which may revolutionize PJI management in the future by eradicating a devastating problem.
Topics: Anti-Infective Agents; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Biofilms; Humans; Immunotherapy; Nanoparticles; Phage Therapy; Photochemotherapy; Prosthesis-Related Infections; Quorum Sensing; Ultrasonic Therapy; Vaccines
PubMed: 31935760
DOI: 10.1055/s-0040-1701214 -
Acta Medica (Hradec Kralove) 2015Ovarian cancer is the fifth most common malignancy in the world's female population and with the highest lethality index among gynecological tumors. The prognosis of... (Review)
Review
Extracorporeal Elimination of Circulating Pegylated Liposomal Doxorubicin (PLD) to Enhance the Benefit of Cytostatic Therapy in Platinum-Resistant Ovarian Cancer Patients.
Ovarian cancer is the fifth most common malignancy in the world's female population and with the highest lethality index among gynecological tumors. The prognosis of metastatic disease is usually poor, especially in platinum-resistant cases. There are several options for the treatment of metastatic disease resistant to platinum derivates (e.g. paclitaxel, topotecan and pegylated liposomal doxorubicin), all of which are considered equipotent. Pegylated liposomal doxorubicin (PLD) is a liposomal form of the anthracycline antibiotic doxorubicin. It is characterized by more convenient pharmacokinetics and a different toxicity profile. Cardiotoxicity, the major adverse effect of conventional doxorubicin, is reduced in PLD as well as hematotoxicity, alopecia, nausea and vomiting. Skin toxicity and mucositis, however, emerge as serious issues since they represent dose and schedule-limiting toxicities. The pharmacokinetics of PLD (prolonged biological half-life and preferential distribution into tumor tissue) provide new possibilities to address these toxicity issues. The extracorporeal elimination of circulating liposomes after PLD saturation in the tumor tissue represents a novel and potent strategy to diminish drug toxicity. This article intends to review PLD characteristics and the importance of extracorporeal elimination to enhance treatment tolerance and benefits.
Topics: Antibiotics, Antineoplastic; Cytostatic Agents; Doxorubicin; Drug Resistance, Neoplasm; Extracorporeal Circulation; Female; Humans; Ovarian Neoplasms; Platinum Compounds; Polyethylene Glycols
PubMed: 26454800
DOI: 10.14712/18059694.2015.84