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Synergistic Anticancer Activity of Topotecan— Cyclin-Dependent Kinase Inhibitor Combinations against Drug-Resistant Small Cell Lung Cancer (SCLC) Cell Lines

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Journal of Cancer Therapy 2013年第8期4卷 47-53页

作者： Gerhard Hamilton ulrike olszewski, Lukas Klameth Ernst Ulsperger Klaus Geissler Ludwig Boltzmann Cluster of Translational Oncology Vienna Austria Ludwig Boltzmann Cluster of Translational Oncology Vienna Austria.

Extended-stage small cell lung cancer (SCLC) responds to platinum/vepeside-based first-line chemotherapy but relapses rapidly as drug-resistant tumor. Topotecan (TPT) is the single chemotherapeutic agent approved for second-line treatment of SCLC. However, the response to TPT is short-lived and novel treatment modalities need to be developed. Sequential treatment of cytotoxic drugs and inhibitors of cyclin-dependent kinases (CDKs) showed promising preclinical anticancer activity and, in the present work, combinations of TPT with CDK inhibitors olomoucine, roscovitine and CDK4I are shown to exhibit synergistic cytotoxic activity against SCLC cell lines. Highest activity was found against TPT-resistant NCI-H417 and DMS153 cell lines and moderate chemosensitizing effects against a primary SCLC cell line and sensitive GLC19 cells at levels of CDK inhibitors which exerted low toxicity. A combination of 0.6 μM TPT with 0.6 μM roscovitine, exhibiting no significant cytotoxicity as single agents, reduced viability of the TPT-resistant NCI-H417 line (IC50 > 10 μM) by 50%. In the TPT resistant cell lines olomoucine and roscovitine, targeting CDK1,2,5,7, were highly effective, whereas in the more sensitive cell lines CDK4I, inhibiting mainly CDK4/6, showed activity. In NCI-417 cells, preincubation with roscovitine for one day proved synergistic with TPT. Thus, in good accordance with previous findings, CDK inhibitors are able to convert SCLC cancer cells which are cell-cycle arrested by a blockade of topoisomerase I by TPT to apoptotic cells. Since nowadays several CDK inhibitors are at various phases of clinical testing their combination with TPT seems to constitute a promising approach to improve second-line chemotherapy in SCLC.

关键词： Small Cell Lung Cancer Chemoresistance Topotecan CDK Inhibitor Olomoucine Roscovitine

Proteomic analysis of ferroptosis pathways reveals a role of CEPT1 in suppressing ferroptosis

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Protein & Cell 2024年第9期15卷 686-703页

作者： Xiaoguang Liu Zhen Chen Yuelong Yan Fereshteh Zandkarimi Litong Nie Qidong Li Amber Horbath Kellen olszewski Lavanya Kondiparthi Chao Mao Hyemin Lee Li Zhuang Masha Poyurovsky Brent RStockwell Junjie Chen Boyi Gan Department of Experimental Radiation Oncology The University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Department of Biological Sciences and Department of Chemistry Columbia UniversityNew YorkNY 10027USA Kadmon Corporation LLC(A Sanofi Company)New YorkNY 10016USA The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences HoustonTX 77030USA The Barer Institute PhiladelphiaPA 19104USA

Ferroptosis has been recognized as a unique cell death modality driven by excessive lipid peroxidation and unbalanced cellular *** this study,we established a protein interaction landscape for ferroptosis pathways through proteomic analyses,and identified choline/ethanolamine phosphotransferase 1(CEPT1)as a lysophosphatidylcholine acyltransferase 3(LPCAT3)-interacting protein that regulates LPCAT3 protein *** contrast to its known role in promoting phospholipid synthesis,we showed that CEPT1 suppresses ferroptosis potentially by interacting with phospholipases and breaking down certain pro-ferroptotic polyunsaturated fatty acid(PUFA)-containing ***,our study reveals a previously unrecognized role of CEPT1 in suppressing ferroptosis.

关键词： proteomics ferroptosis CEPT1 LPCAT3

NADPH debt drives redox bankruptcy:SLC7A11/xCT-mediated cystine uptake as a double-edged sword in cellular redox regulation

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Genes & Diseases 2021年第6期8卷 731-745页

作者： Xiaoguang Liu Yilei Zhang Li Zhuang Kellen olszewski Boyi Gan Department of Experimental Radiation Oncology The University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Kadmon Corporation LLCNew YorkNY 10016USA The University of Texas MD Anderson UTHealth Graduate School of Biomedical SciencesHoustonTX 77030USA

Cystine/glutamate antiporter solute carrier family 7 member 11(SLC7A11;also known as xCT)plays a key role in antioxidant defense by mediating cystine uptake,promoting glutathione synthesis,and maintaining cell survival under oxidative stress *** studies showed that,to prevent toxic buildup of highly insoluble cystine inside cells,cancer cells with high expression of SLC7A11(SLC7A11high)are forced to quickly reduce cystine to more soluble cysteine,which requires substantial NADPH supply from the glucose-pentose phosphate pathway(PPP)route,thereby inducing glucose-and PPP-dependency in SLC7A11high cancer *** glucose supply to SLC7A11high cancer cells results in significant NADPH“debt”,redox“bankruptcy”,and subsequent cell *** review summarizes our current understanding of NADPH-generating and-consuming pathways,discusses the opposing role of SLC7A11 in protecting cells from oxidative stresseinduced cell death such as ferroptosis but promoting glucose starvationeinduced cell death,and proposes the concept that SLC7A11-mediated cystine uptake acts as a double-edged sword in cellular redox regulation.A detailed understanding of SLC7A11 in redox biology may identify metabolic vulnerabilities in SLC7A11high cancer for therapeutic targeting.

关键词： Cysteine Cystine NADPH Pentose phosphate pathway SLC7A11 xCT

COVID-19 outbreak and endoscopy: Considerations in patients encountered in a foregut surgery practice

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World Journal of Gastrointestinal Surgery 2020年第5期12卷 197-202页

作者： Tanya olszewski Andrew D Grubic Shahin Ayazi Blair A Jobe Esophageal and Lung Institute Department of SurgeryAllegheny Health NetworkPittsburghPA 15224United States

Severe acute respiratory syndrome coronavirus has become a critical challenge to global *** the arrival of coronavirus disease 2019 in the United States,several government agencies and professional societies have issued guidelines to healthcare systems and medical *** is a substantial portion of the practice of many general surgeons in the United *** upper endoscopy,manipulation of the upper aerodigestive tract can turn the droplets to an aerosolized form and increase the likelihood of transmission and therefore is considered a high-risk *** this article we review some aspects of the coronavirus disease 2019 outbreak that are relevant to practice of surgical *** emphasis of this communication is on the mode of transmission,previous experiences during other coronavirus outbreaks and society *** then highlight the changes that we have made to our practice to incorporate these factors to improve the safety of patients,health care providers,and community as a whole.

关键词： SARS-CoV-2 COVID-19 Endoscopy Pandemic Best practice Personal protection equipment

Effect of a Non-Zero Velocity of the Motion Frame on the Kinetic Energy of a Free Particle Examined with the Aid of the Relativistic Mechanics

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World Journal of Mechanics 2021年第1期11卷 1-6页

作者： Stanislaw olszewski Institute of Physical Chemistry Polish Academy of Sciences Warsaw Poland

The paper examines the change of the relativistic kinetic energy of a free particle due to the velocity change of the motion frame in a special case when this reduction leads to the kinetic energy equal to zero. The difference of velocities gives a functional dependent solely on the velocity frame and original velocity of the particle. An analysis applied to the functional gives simple formulae for the extremal values of the mentioned velocity parameters. In the next step, solutions of the equation presented with the functional provide us with the velocities necessary for the vanishing property of the kinetic energy. A characteristic point is that a condition of the velocity of the motion frame smaller than the velocity of light is obtained directly in the applied formalism. This property holds with no reference done to the well-known postulate of the dominant value of the light velocity entering the relativity theory.

关键词： Relativistic Kinetic Energy Reduction of the Particle Velocity due to the Velocity of the Motion Frame

Quanta of the Phase-Space Areas Given by Intervals of Energy and Time Associated with Electron Transitions

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Journal of Modern Physics 2017年第8期8卷 1158-1174页

作者： Stanislaw olszewski Institute of Physical Chemistry Polish Academy of SciencesWarsawPoland

The paper examines the energy of electron transitions in an emission process and the time intervals necessary for that process. For simple quantum systems, the both parameters—that of energy and time—depend on the difference Δn of the quantum numbers n labelling the beginning and end state of emission. It is shown that the phase-space areas formed by products of energy and time involved in the emission can be represented as a quadratic function of Δn multiplied by the Planck constant h.

关键词： Electron Transitions Their Energies and Transition Times Quanta of the Phase-Space Areas of Energy and Time

Circular Scale of Time and Construction of the Schrodinger Perturbation Series for Energy Made Simple

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Journal of Modern Physics 2017年第9期8卷 1650-1684页

作者： Stanislaw olszewski Institute of Physical Chemistry Polish Academy of SciencesWarsawPoland

Physically the examined perturbation problem can be regarded as a set of collision events of a time-independent perturbation potential with a quantum system. As an effect of collisions there is an expected definite change of energy of an initially unperturbed state of the system to some stationary perturbed state. The collision process certainly occupies some intervals of time which, however, do not enter the formalism. A striking property is the result of a choice of the sequence of collisions according to the applied circular scale of time: the scale produces almost automatically the energy terms predicted by the Schrödinger perturbation theory which usually is attained in virtue of complicated mathematical transformations. Beyond of the time scale and its rules—strictly connected with the perturbation order N introduced by Schrödinger—a partition process of the number N-1 is applied. This process, combined with contractions of the time points on the scale, provides us precisely with the perturbation terms entering the Schrödinger theory.

关键词： Circular Scale of Time Schrodinger Perturbation Series for Energy Non-Degenerate Quantum State

Bohr’s Spectrum of Quantum States in the Atomic Hydrogen Deduced from the Uncertainty Principle for Energy and Time

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Journal of Modern Physics 2014年第14期5卷 1264-1271页

作者： Stanislaw olszewski Institute of Physical Chemistry Polish Academy of Sciences Warsaw Poland

A modified uncertainty principle coupling the intervals of energy and time can lead to the shortest distance attained in course of the excitation process, as well as the shortest possible time interval for that process. These lower bounds are much similar to the interval limits deduced on both the experimental and theoretical footing in the era when the Heisenberg uncertainty principle has been developed. In effect of the bounds existence, a maximal nuclear charge Ze acceptable for the Bohr atomic ion could be calculated. In the next step the velocity of electron transitions between the Bohr orbits is found to be close to the speed of light. This result provides us with the energy spectrum of transitions similar to that obtained in the Bohr’s model. A momentary force acting on the electrons in course of their transitions is estimated to be by many orders larger than a steady electrostatic force existent between the atomic electron and the nucleus.

关键词： Uncertainty Principle for Energy and Time Bohr’s Spectrum of Quantum levels in the Hydrogen Atom

Non-Probabilistic Approach to the Time of Energy Emission in Small Quantum Systems

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Journal of Modern Physics 2015年第9期6卷 1277-1288页

作者： Stanislaw olszewski Institute of Physical Chemistry Polish Academy of SciencesKasprzakaWarsawPoland

The energy emitted by an electron in course of its transition between two quantum levels can be considered as a dissipated energy. This energy is obtained within a definite interval of time. The problem of the size of the time interval necessary for transitions is examined both on the ground of the quantum approach as well as classical electrodynamics. It is found that in fact the emission time approaches the time interval connected with acceleration of a classical velocity of the electron particle from one of its quantum levels to a neighbouring one.

关键词： Dissipated Energy and Time Intervals of the Quantum Transitions Electron Acceleration in Simple Quantum Systems Considered as a Test of the Theory