Recent developments in topoisomerase-targeted cancer chemotherapy

Hevener, Kirk E.; Verstak, Tatsiana A.; Lutat, Katie E.; Riggsbee, Daniel L.; Mooney, Jeremiah W.

doi:10.1016/j.apsb.2018.07.008

Cited by 197 publications

(150 citation statements)

References 101 publications

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“…Camptothecin derivatives (CPTs) such as topotecan, irinotecan and belotecan are common chemotherapy agents that are used for the treatment of cancers. These therapeutic agents are used either as monotherapy or in combination with other anticancer drugs for the treatments of small cell lung cancer, metastatic colon and rectal carcinoma [1,2]. Belotecan was recently approved in South Korea for non-small-cell lung cancer and ovarian cancer [2].…”

Section: Introductionmentioning

confidence: 99%

The Development of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges

et al. 2019

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Eleven amide and thioamide derivatives with monoterpene and adamantine substituents were synthesised. They were tested for their activity against the tyrosyl-DNA phosphodiesterase 1 DNA (Tdp1) repair enzyme with the most potent compound 47a, having an IC50 value of 0.64 M. When tested in the A-549 lung adenocarcinoma cell line, no or very limited cytotoxic effect was observed for the ligands. However, in conjunction with topotecan, a well-established Topoisomerase 1 (Top1) poison in clinical use against cancer, derivative 46a was very cytotoxic at 5 M concentration, displaying strong synergism. This effect was only seen for 46a (IC50—3.3 M) albeit some other ligands had better IC50 values. Molecular modelling into the catalytic site of Tdp1 predicted plausible binding mode of 46a, effectively blocking access to the catalytic site.

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Section: Introductionmentioning

confidence: 99%

The Development of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges

et al. 2019

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“…We decided to focus on three synergistic drugs discovered in the screen: cabozantinib (receptor tyrosine kinase inhibitor), clofarabine (an RNR inhibitor) [36] and vinblastine (microtubule inhibitor/G2 arresting agent) [37–40]. We also validated three drugs that demonstrated a significant loss of potency in cells lacking HDJ2: sorafenib (a VEGFR-2 inhibitor) [41], omacetaxine mepesuccinate (more commonly known as homoharringtonine, a protein translation inhibitor) [42] and idarubicin (topoisomerase II inhibitor) [43]. To determine synergy in a quantitative manner, we calculated drug synergy (Combination Index values, CI) between 116-9e and either synergistic or antagonistic drugs hits across a broad range of concentrations using the Chou-Talalay method [44].…”

Section: Resultsmentioning

confidence: 99%

Chemogenomic screening Identifies the Hsp70 Co-chaperone HDJ2 as a Hub for Anticancer Drug Resistance

Nitika

Blackman

Knighton

et al. 2019

Preprint

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24Heat shock protein 70 (Hsp70) is an important molecular chaperone that regulates 25 oncoprotein stability and tumorigenesis. However, attempts to develop anti-chaperone 26 drugs targeting molecules such as Hsp70 have been hampered by toxicity issues. Hsp70 27 is regulated by a suite of co-chaperone molecules that bring "clients" to the primary 28 chaperone for efficient folding. Therefore, rather than targeting Hsp70 itself, here we have 29 examined the feasibility of inhibiting the co-chaperone HDJ2, a member of the J domain 30 protein family, as a novel anticancer strategy. We found HDJ2 to be upregulated in a 31 variety of cancers, suggesting a role in malignancy. To confirm this role, we screened the 32 NIH Approved Oncology collection for chemical-genetic interactions with loss of HDJ2 in 33 cancer. 41 compounds showed strong synergy with HDJ2 loss, whereas 18 dramatically 34 lost potency. Several of these hits were validated using a HDJ2 inhibitor (116-9e) in 35 castration-resistant prostate cancer cell (CRPC) and spheroid models. Taken together, 36 these results confirmed that HDJ2 is a hub for anticancer drug resistance and that HDJ2 37 inhibition may be a potent strategy to sensitize cancer cells to current and future 38 therapeutics. 39 40 41 42 104 Materials and Methods 105 Cell culture. The HAP1 Chronic Myelogenous Leukemia cancer cell line and HDJ2 106 Knockout cell line was purchased from Horizon Discovery and were cultured in Iscove's 107 Modified Eagle Medium (Invitrogen) with 10% fetal bovine serum (Gibco), 100 units/ml 108 penicillin, and 100 μg/ml streptomycin at 5% CO2 and 37° C. The LNCaP cancer cell line 109 was purchased from ATCC and were cultured in RPMI-1640 medium (Invitrogen) with 110 10% fetal bovine serum (FBS, Clontech), 100 units/ml penicillin, and 100 μg/ml 111 streptomycin at 5% CO2 and 37° C. 112 6 Drug Screening. Approved Oncology Drug plates consisting of the most current FDA 113 approved anticancer drugs were obtained from National Cancer Institute (NCI). For 114 experiments delineating the synergy between the loss of HDJ2 and approved anticancer 115 drug, HAP1 cells and HAP1 (HDJ2 KO) cells were plated in growth media at 20% 116 confluency 1 day prior to drug treatment. On Day 1 of treatment, cells were treated with 117 DMSO (control), Approved oncology anticancer drugs at 50 µM for 72 hours. Following 118 drug treatments, Cell Titer-Glo reagent was added directly to the wells according to 119 manufacturer's instructions. The luminescence was measured on Bio-Tek Plate reader. 120 Luminescence reading was normalized to and expressed as a relative percentage of the 121 plate averaged DMSO control. The data shown are the mean and SEM of three 122 independent biological replicates. 123 Combination index (CI) calculations. For IC50 calculations, LNCaP cells were seeded 124 in triplicates in 96-well white bottom Nunc plates in growth media at 20% confluency 1 day 125 prior to initiation of drug treatment. On Day 1 of treatment, cells were treated with DMSO 126 (control) and ten ...

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“…For instance, simultaneous blocking of both topoisomerase I and II showed synergies in all the patient samples. While this combination might provide an opportunity to effectively co-target AML rescue pathways, as inhibition of either of the enzymes alone may lead to increase in the expression of the other, hence resulting in treatment of resistance 24 , the sequential or simultaneous co-inhibition of topoisomerase I and II by compounds forming DNA lesions has shown severe side effects 60 . Therefore, dual inhibitors with a longer half-life and improved binding efficacy (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…Two such common combinations that showed high synergy (ZIP > 5) in the whole-well viability assay across all the samples included camptothecin (topoisomerase I inhibitor) combined with etoposide (topoisomerase II inhibitor), and venetoclax (Bcl-2 inhibitor) combined with vistusertib (mTOR inhibitor). While simultaneous blocking of both topoisomerase I and II may lead to overlapping toxicities 24 , it has been shown that co-targeting of both Bcl-2 and mTOR pathway triggers synergistic apoptosis and enhances drug-induced cytotoxicity by suppressing MCL-1 in leukemic cells 25 . The predictive approach also identified the ruboxistaurin-ipatasertib combination as synergistic in all but one sample (in the refractory AML3 sample the combination was additive with ZIP = 2.3).…”

Section: Patient-specific Combinations Show High Overall Synergy and mentioning

confidence: 99%

Patient-tailored design of AML cell subpopulation-selective drug combinations

Ianevski

Lahtela

Javarappa

et al. 2020

Preprint

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The extensive primary and secondary drug resistance in acute myeloid leukemia (AML) requires rational approaches to design personalized combinatorial treatments that exploit patient-specific therapeutic vulnerabilities to optimally target disease-driving AML cell subpopulations. However, the large number of AML-relevant drug combinations makes the testing impossible in scarce primary patient cells. This combinatorial problem is further exacerbated by the translational challenge of how to design such personalized and selective drug combinations that do not only show synergistic effect in overall AML cell killing but also result in minimal toxic side effects on non-malignant cells. To solve these challenges, we implemented a systematic computational-experimental approach for identifying potential drug combinations that have a desired synergy-efficacy-toxicity balance. Our mechanism-agnostic approach combines single-cell RNA-sequencing (scRNA-seq) with ex vivo single-agent viability testing in primary patient cells. The data integration and predictive modelling are carried out at a single-cell resolution by means of a machine learning model that makes use of compound-target interaction networks to narrow down the massive search space of potentially effective drug combinations. When applied to two diagnostic and two refractory AML patient cases, each having a different genetic background, our integrated approach predicted a number of patient-specific combinations that were shown to result not only in synergistic cancer cell inhibition but were also capable of targeting specific AML cell subpopulations that emerge in differing stages of disease pathogenesis or treatment regimens. Overall, 53% of the 59 predicted combinations were experimentally confirmed to show synergy, and 83% were non-antagonistic, as validated with viability assays, which is a significant improvement over the success rate of randomly guessing a synergistic drug combination (5%). Importantly, 67% of the predicted combinations showed low toxicity to non-malignant cells, as validated with flow-based population assays, suggesting their selective killing of AML cell populations. Our data-driven approach provides an unbiased means for systematic prioritization of patient-specific drug combinations that selectively inhibit AML cells and avoid co-inhibition of non-malignant cells, thereby increasing their likelihood for clinical translation. The approach uses only a limited number of patient primary cells, and it is widely applicable to hematological cancers that are accessible for scRNA-seq profiling and ex vivo compound testing.

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Recent developments in topoisomerase-targeted cancer chemotherapy

Cited by 197 publications

References 101 publications

The Development of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges

The Development of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges

Chemogenomic screening Identifies the Hsp70 Co-chaperone HDJ2 as a Hub for Anticancer Drug Resistance

Patient-tailored design of AML cell subpopulation-selective drug combinations

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