scholarly journals Mathematical Approach to Differentiate Spontaneous and Induced Evolution to Drug Resistance During Cancer Treatment

2019 ◽  
pp. 1-20 ◽  
Author(s):  
James M. Greene ◽  
Jana L. Gevertz ◽  
Eduardo D. Sontag
Keyword(s):  
Drug Resistance ◽  
Cancer Treatment ◽  
Treatment Resistance ◽  
Drug Dose ◽  
Modeling Framework ◽  
Drug Induced ◽  
Treatment Protocols ◽  
Genetic Changes ◽  
Induce Resistance

Purpose Drug resistance is a major impediment to the success of cancer treatment. Resistance is typically thought to arise from random genetic mutations, after which mutated cells expand via Darwinian selection. However, recent experimental evidence suggests that progression to drug resistance need not occur randomly, but instead may be induced by the treatment itself via either genetic changes or epigenetic alterations. This relatively novel notion of resistance complicates the already challenging task of designing effective treatment protocols. Materials and Methods To better understand resistance, we have developed a mathematical modeling framework that incorporates both spontaneous and drug-induced resistance. Results Our model demonstrates that the ability of a drug to induce resistance can result in qualitatively different responses to the same drug dose and delivery schedule. We have also proven that the induction parameter in our model is theoretically identifiable and propose an in vitro protocol that could be used to determine a treatment’s propensity to induce resistance.

scholarly journals A mathematical approach to differentiate spontaneous and induced evolution to drug resistance during cancer treatment

2017 ◽  
Author(s):  
James M. Greene ◽  
Jana L. Gevertz ◽  
Eduardo D. Sontag
Keyword(s):  
Drug Resistance ◽  
Cancer Treatment ◽  
Treatment Resistance ◽  
Drug Dose ◽  
Modeling Framework ◽  
Drug Induced ◽  
Treatment Protocols ◽  
Genetic Changes ◽  
Induce Resistance

AbstractDrug resistance is a major impediment to the success of cancer treatment. Resistance is typically thought to arise through random genetic mutations, after which mutated cells expand via Darwinian selection. However, recent experimental evidence suggests that the progression to drug resistance need not occur randomly, but instead may be induced by the treatment itself, through either genetic changes or epigenetic alterations. This relatively novel notion of resistance complicates the already challenging task of designing effective treatment protocols. To better understand resistance, we have developed a mathematical modeling framework that incorporates both spontaneous and drug-induced resistance. Our model demonstrates that the ability of a drug to induce resistance can result in qualitatively different responses to the same drug dose and delivery schedule. We have also proven that the induction parameter in our model is theoretically identifiable, and proposed an in vitro protocol which could be used to determine a treatment’s propensity to induce resistance.

scholarly journals Hypoxia-Mediated Down-Regulation of Bid and Bax in Tumors Occurs via Hypoxia-Inducible Factor 1-Dependent and -Independent Mechanisms and Contributes to Drug Resistance

2004 ◽  
Vol 24 (7) ◽  
pp. 2875-2889 ◽  
Author(s):  
Janine T. Erler ◽  
Christopher J. Cawthorne ◽  
Kaye J. Williams ◽  
Marianne Koritzinsky ◽  
Bradley G. Wouters ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Solid Tumors ◽  
Hypoxia Inducible Factor ◽  
Oxygen Deprivation ◽  
Translation Efficiency ◽  
Down Regulation ◽  
Drug Induced ◽  
Human Colon Cancer ◽  
Hypoxia Inducible Factor 1

ABSTRACT Solid tumors with disorganized, insufficient blood supply contain hypoxic cells that are resistant to radiotherapy and chemotherapy. Drug resistance, an obstacle to curative treatment of solid tumors, can occur via suppression of apoptosis, a process controlled by pro- and antiapoptotic members of the Bcl-2 protein family. Oxygen deprivation of human colon cancer cells in vitro provoked decreased mRNA and protein levels of proapoptotic Bid and Bad. Hypoxia-inducible factor 1 (HIF-1) was dispensable for the down-regulation of Bad but required for that of Bid, consistent with the binding of HIF-1α to a hypoxia-responsive element (positions −8484 to −8475) in the bid promoter. Oxygen deprivation resulted in proteosome-independent decreased expression of Bax in vitro, consistent with a reduction in global translation efficiency. The physiological relevance of Bid and Bax down-regulation was confirmed in tumors in vivo. Oxygen deprivation resulted in decreased drug-induced apoptosis and clonogenic resistance to agents with different mechanisms of action. The contribution of Bid and/or Bax down-regulation to drug responsiveness was demonstrated by the relative resistance of normoxic cells that had no or reduced expression of Bid and/or Bax and by the finding that forced expression of Bid in hypoxic cells resulted in increased sensitivity to the topoisomerase II inhibitor etoposide.

scholarly journals MiR-142-3p Overexpression Increases Chemo-Sensitivity of NSCLC by Inhibiting HMGB1-Mediated Autophagy

2017 ◽  
Vol 41 (4) ◽  
pp. 1370-1382 ◽  
Author(s):  
Yuqing Chen ◽  
Xin Zhou ◽  
Jianou Qiao ◽  
Aihua Bao
Keyword(s):  
Drug Resistance ◽  
Therapeutic Potential ◽  
High Mobility ◽  
In Silico Analysis ◽  
Luciferase Reporter ◽  
Hmgb1 Protein ◽  
Drug Induced ◽  
Hmgb1 Expression

Background: Non-small-cell lung cancer (NSCLC) is a deadly cancer with high mortality rate. Drug resistance represents a main obstacle in NSCLC treatment. High mobility group box-1 (HMGB1) protein promotes drug resistance in NSCLC cells by activating protective autophagy. Methods: In the current study, we investigated the regulatory role of microRNA-142-3p (miR-142-3p) in HMGB1-mediated autophagy of NSCLC cells and its impact on drug resistance of NSCLC in vitro and in vivo. HMGB1 was identified as a putative target gene of miR-142-3p by in silico analysis. Our luciferase reporter assay results confirmed that miR-142-3p directly targets the 3’-UTR of HMGB1 in NSCLC cells. Results: MiR-142-3p overexpression suppressed while miR-142-3p knockdown increased HMGB1 mRNA and protein expression. Starvation induced HMGB1 expression and activated autophagy in NSCLC cells. The starvation-induced autophagy was inhibited by miR-142-3p overexpression or HMGB1 knockdown. Moreover, miR-142-3p overexpression or HMGB1 knockdown increased PI3K, Akt, and mTOR phosphorylation. Inhibition of PI3K or mTOR restored starvation-induced autophagy inhibited by miR-142-3p overexpression or HMGB1 knockdown. Conclusions: These results demonstrated that miR-142-3p regulates starvation-induced autophagy of NSCLC cells by directly downregulating HMGB1 and subsequently activating the PI3K/Akt/mTOR pathway. Further, miR-142-3p overexpression inhibited anticancer drug-induced autophagy and increased chemo-sensitivity of NSCLC in vitro and in vivo. These findings shed light on the therapeutic potential of miR-142-3p in combating acquired NSCLC chemo-resistance.

Heterogeneity and Phenotypic Instability of Chemotherapeutic and Immunologic Sensitivity in Murine and Human Melanoma Cell Clones

1992 ◽  
Vol 78 (1) ◽  
pp. 5-9 ◽  
Author(s):  
Rosanna Supino ◽  
Monica Rodolfo ◽  
Mariangela Mariani ◽  
Elena Mapelli
Keyword(s):  
Drug Resistance ◽  
Melanoma Cell ◽  
Drug Sensitivity ◽  
Human Melanoma ◽  
Lak Cells ◽  
Human Melanoma Cell ◽  
Drug Resistant ◽  
Drug Induced ◽  
Resistant Cells

The aim of the present study was to examine the phenotypic heterogeneity of murine and human melanoma cell lines with particular reference to anticancer drug sensitivity, growth pattern and susceptibility to lysis by lymphokine (rIL2) activated killer (LAK cells). Clones selected for a different drug sensitivity were tested to evaluate the stability of such properties after different in vitro passages. A possible relationship between drug sensitivity and LAK susceptibility was also analyzed. The results indicated a high heterogeneity in murine and in human melanoma clones for all the parameters. However, drug sensitivity, which was stable although for only a few passages in an untreated human melanoma, was highly unstable in murine naturally or drug-induced resistant cells. Finally, whereas human drug-resistant clones were sensitive to lysis by LAK cells and an inverse correlation was found with the level of drug resistance, murine clones appeared to be LAK sensitive, and no correlation was found between the level of drug resistance and LAK sensitivity. Our data indicate a different stability in drug response of human and murine cells and a different behaviour of human and murine drug-resistant cells in response to LAK lysis.

scholarly journals A new model isolates glioblastoma clonal interactions and reveals unexpected modes for regulating motility, proliferation, and drug resistance

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Justin B Davis ◽  
Sreshta S Krishna ◽  
Ryan Abi Jomaa ◽  
Cindy T. Duong ◽  
Virginia Espina ◽  
...  
Keyword(s):  
Drug Resistance ◽  
De Novo ◽  
Functional Model ◽  
3D Culture ◽  
Interaction Network ◽  
Treatment Resistance ◽  
Cell Contact ◽  
Clonal Heterogeneity ◽  
Single Clone

AbstractTumor clonal heterogeneity drives treatment resistance. But robust models are lacking that permit eavesdropping on the basic interaction network of tumor clones. We developed an in vitro, functional model of clonal cooperation using U87MG glioblastoma cells, which isolates fundamental clonal interactions. In this model pre-labeled clones are co-cultured to track changes in their individual motility, growth, and drug resistance behavior while mixed. This highly reproducible system allowed us to address a new class of fundamental questions about clonal interactions. We demonstrate that (i) a single clone can switch off the motility of the entire multiclonal U87MG cell line in 3D culture, (ii) maintenance of clonal heterogeneity is an intrinsic and influential cancer cell property, where clones coordinate growth rates to protect slow growing clones, and (iii) two drug sensitive clones can develop resistance de novo when cooperating. Furthermore, clonal communication for these specific types of interaction did not require diffusible factors, but appears to depend on cell-cell contact. This model constitutes a straightforward but highly reliable tool for isolating the complex clonal interactions that make up the fundamental “hive mind” of the tumor. It uniquely exposes clonal interactions for future pharmacological and biochemical studies.

scholarly journals A recent development of new therapeutic agents and novel drug targets for cancer treatment

2021 ◽  
Vol 9 ◽  
pp. 205031212110670
Author(s):  
Zemene Demelash Kifle ◽  
Meklit Tadele ◽  
Eyerusalem Alemu ◽  
Tadele Gedamu ◽  
Akeberegn Gorems Ayele
Keyword(s):  
Drug Resistance ◽  
Cancer Treatment ◽  
Drug Targets ◽  
Therapeutic Agents ◽  
Chemotherapeutic Agents ◽  
Cross Resistance ◽  
Drug Induced ◽  
Induced Apoptosis ◽  
Novel Drug ◽  
Novel Drug Targets

Despite recent advances in cancer diagnosis, prevention, detection, as well as management, the disease is expected to be the top cause of death globally. The chemotherapy approach for cancer has become more advanced in its design, yet no medication can cure enough against all types of cancer and its stage. Thus, this review aimed to summarize a recent development of new therapeutic agents and novel drug targets for the treatment of cancer. Several obstacles stand in the way of effective cancer treatment and drug development, including inaccessibility of tumor site by appropriate drug concentration, debilitating untoward effects caused by non-selective tissue distribution of chemotherapeutic agents, and occurrence of drug resistance, which leads to cross-resistance to a variety of drugs. Resistance to treatment with anticancer drugs results from multiple factors and the most common reason for acquiring drug resistance is marking and expelling drugs that prevent cancer cells to be targeted by chemotherapeutic agents. Moreover, insensitivity to drug-induced apoptosis, alteration, and mutation of drug target and interference/change of DNA replication are other main causes of treatment failure.

scholarly journals In Vitro Activity of ABT-773 againstLegionella pneumophila, Its Pharmacokinetics in Guinea Pigs, and Its Use to Treat Guinea Pigs with L. pneumophila Pneumonia

2001 ◽  
Vol 45 (10) ◽  
pp. 2685-2690 ◽  
Author(s):  
Paul H. Edelstein ◽  
F. Higa ◽  
Martha A. C. Edelstein
Keyword(s):  
Guinea Pig ◽  
Legionella Pneumophila ◽  
Half Life ◽  
Guinea Pigs ◽  
Clinical Effectiveness ◽  
Drug Dose ◽  
Drug Induced ◽  
Time Curve ◽  
Legionnaires Disease

ABSTRACT The activity of ABT-773 was studied against extracellular and intracellular Legionella pneumophila and for the treatment of guinea pigs with L. pneumophila pneumonia. The ABT-773 MIC at which 50% of isolates are inhibited (MIC50) for 20 different Legionella sp. strains was 0.016 μg/ml, whereas the MIC50s of clarithromycin and erythromycin were 0.032 and 0.125 μg/ml, respectively. ABT-773 (1 μg/ml) was bactericidal for two L. pneumophila strains grown in guinea pig alveolar macrophages. In contrast, erythromycin and clarithromycin had easily reversible static activity only. Therapy studies of ABT-773 and erythromycin were performed with guinea pigs with L. pneumophilapneumonia. When ABT-773 was given to infected guinea pigs by the intraperitoneal route (10 mg/kg of body weight), mean peak levels in plasma were 0.49 μg/ml at 0.5 h and 0.30 μg/ml at 1 h postinjection. The terminal half-life phase of elimination from plasma was 0.55 h, and the area under the concentration-time curve from 0 to 24 h (AUC0–24) was 0.65 μg · h/ml. For the same drug dose, mean levels in the lung were 15.9 and 13.2 μg/g at 0.5 and 1 h, respectively, with a half-life of 0.68 h and an AUC0–24 of 37.0 μg · h/ml. Ten of 15 L. pneumophila-infected guinea pigs treated with ABT-773 (15 mg/kg/dose given intraperitoneally once daily) for 5 days survived for 9 days post-antimicrobial therapy, as did 14 of 15 guinea pigs treated with erythromycin (30 mg/kg given intraperitoneally twice daily) for 5 days. All of the ABT-773-treated animals that died appeared to do so because of drug-induced peritonitis rather than overwhelming pneumonia. None of 12 animals treated with saline survived. ABT-773 is as effective as erythromycin against L. pneumophila in infected macrophages and in a guinea pig model of Legionnaires' disease. These data support studies of the clinical effectiveness of ABT-773 for the treatment of Legionnaires' disease.

Melatonin: From Basic Research to Cancer Treatment Clinics

2002 ◽  
Vol 20 (10) ◽  
pp. 2575-2601 ◽  
Author(s):  
Vijayalaxmi ◽  
Charles R. Thomas ◽  
Russel J. Reiter ◽  
Terence S. Herman
Keyword(s):  
Cancer Treatment ◽  
Basic Research ◽  
Free Radical Scavenger ◽  
Radical Scavenger ◽  
Secretory Product ◽  
Drug Induced ◽  
Radiation Induced ◽  
Laboratory Investigations

ABSTRACT: Melatonin, the chief secretory product of the pineal gland, is a direct free radical scavenger, an indirect antioxidant, as well as an important immunomodulatory agent. In both in vitro and in vivo investigations, melatonin protected healthy cells from radiation-induced and chemotherapeutic drug–induced toxicity. Furthermore, several clinical studies have demonstrated the potential of melatonin, either alone or in combination with traditional therapy, to yield a favorable efficacy to toxicity ratio in the treatment of human cancers. This study reviews the literature from laboratory investigations that document the antioxidant and oncostatic actions of melatonin and summarizes the evidence regarding the potential use of melatonin in cancer treatment. This study also provides rationale for the design of larger translational research–based clinical trials.

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