Combination of HDAC and topoisomerase inhibitors in small cell lung cancer

Gray, Jhanelle E.; Cubitt, Christopher L.; Zhang, Shumin; Chiappori, Alberto

doi:10.4161/cbt.19848

Cited by 47 publications

(28 citation statements)

References 40 publications

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“…The half-maximal inhibitory concentration (IC 50 ; concentration of drug required for a 50% reduction in growth/viability) values and combination index (CI) values of the SINE molecules when used alone and in combination with other drugs were determined by a high-throughput CellTiter-Blue (Promega) cell viability assay as described previously 28. Cell cultures grown at log-phase densities (2 x 10 5 /mL) were used to determine IC 50 values, and cells grown at plateau densities (3 x 10 6 /mL) were used to determine synergistic activity.…”

Section: Methodsmentioning

confidence: 99%

CRM1 Inhibition Sensitizes Drug Resistant Human Myeloma Cells to Topoisomerase II and Proteasome Inhibitors both In Vitro and Ex Vivo

Turner¹,

Dawson²,

Emmons³

et al. 2013

J. Cancer

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Multiple myeloma (MM) remains an incurable disease despite improved treatments, including lenalidomide/pomalidomide and bortezomib/carfilzomib based therapies and high-dose chemotherapy with autologous stem cell rescue. New drug targets are needed to further improve treatment outcomes. Nuclear export of macromolecules is misregulated in many cancers, including in hematological malignancies such as MM. CRM1 (chromosome maintenance protein-1) is a ubiquitous protein that exports large proteins (>40 kDa) from the nucleus to the cytoplasm. We found that small-molecule Selective Inhibitors of Nuclear Export (SINE) prevent CRM1-mediated export of p53 and topoisomerase IIα (topo IIα). SINE's CRM1-inhibiting activity was verified by nuclear-cytoplasmic fractionation and immunocytochemical staining of the CRM1 cargoes p53 and topo IIα in MM cells. We found that SINE molecules reduced cell viability and induced apoptosis when used as both single agents in the sub-micromolar range and when combined with doxorubicin, bortezomib, or carfilzomib but not lenalidomide, melphalan, or dexamethasone. In addition, CRM1 inhibition sensitized MM cell lines and patient myeloma cells to doxorubicin, bortezomib, and carfilzomib but did not affect peripheral blood mononuclear or non-myeloma bone marrow mononuclear cells as shown by cell viability and apoptosis assay. Drug resistance induced by co-culture of myeloma cells with bone marrow stroma cells was circumvented by the addition of SINE molecules. These results support the continued development of SINE for patients with MM.

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Section: Methodsmentioning

confidence: 99%

CRM1 Inhibition Sensitizes Drug Resistant Human Myeloma Cells to Topoisomerase II and Proteasome Inhibitors both In Vitro and Ex Vivo

Turner¹,

Dawson²,

Emmons³

et al. 2013

J. Cancer

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“…This thus prompted the execution of a clinical phase I trial; it has just been completed and the final results are still pending. Studies have reported that vorinostat in combination with topotecan demonstrated synergistic anticancer effects in SCLC [24, 25]. However, information regarding the application of vorinostat treatments is still limited.…”

Section: Introductionmentioning

confidence: 99%

Vorinostat enhances the cisplatin-mediated anticancer effects in small cell lung cancer cells

et al. 2016

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BackgroundVorinostat, a histone deacetylase (HDAC) inhibitor, is a promising agent for cancer therapy. Combining vorinostat with cisplatin may relax the chromatin structure and facilitate the accessibility of cisplatin, thus enhancing its cytotoxicity. Studies have not yet investigated the effects of the combination of vorinostat and cisplatin on small cell lung cancer (SCLC).MethodsWe first assessed the efficacy of vorinostat with etoposide/cisplatin (EP; triple combination) and then investigated the effects of cotreatment with vorinostat and cisplatin on H209 and H146 SCLC cell lines. The anticancer effects of various combinations were determined in terms of cell viability, apoptosis, cell cycle distribution, and vorinostat-regulated proteins. We also evaluated the efficacy of vorinostat/cisplatin combination in H209 xenograft nude mice.ResultsOur data revealed that the triple combination engendered a significant reduction of cell viability and high apoptotic cell death. In addition, vorinostat combined with cisplatin enhanced cell growth inhibition, induced apoptosis, and promoted cell cycle arrest. We observed that the acetylation levels of histone H3 and α-tubulin were higher in combination treatments than in vorinostat treatment alone. Moreover, vorinostat reduced the expression of thymidylate synthase (TS), and TS remained inhibited after cotreament with cisplatin. Furthermore, an in vivo study revealed that the combination of vorinostat and cisplatin significantly inhibited tumor growth in xenograft nude mice (tumor growth inhibition T/C% = 20.5 %).ConclusionsCombined treatments with vorinostat promote the cytotoxicity of cisplatin and induce the expression of vorinostat-regulated acetyl proteins, eventually enhancing antitumor effects in SCLC cell lines. Triple combinations with a low dosage of cisplatin demonstrate similar therapeutic effects. Such triple combinations, if applied clinically, may reduce the undesired adverse effects of cisplatin. The effects of the combination of vorinostat and cisplatin should be evaluated further before conducting clinical trials for SCLC treatment.

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“…Hence, we can compare these simulated outcomes to the experimental results showing cell cycle phase distributions over time to pinpoint the right combination of model parameters or to narrow down the possible region in the model parameter space by eliminating unlikely combinations. The drug response curves, which are typically used in the drug testing experiments [78,79,80], can be used to further calibrate our model. Figure 13B displays dosage response curves of five different hypothetical drugs which are represented by five pairs of inhibition parameters (from Figure 13A).…”

Section: Discussionmentioning

confidence: 99%

The formation of tight tumor clusters affects the efficacy of cell cycle inhibitors: A hybrid model study

Kim

Reed

Rejniak

2014

Journal of Theoretical Biology

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Cyclin-dependent kinases (CDKs) are vital in regulating cell cycle progression, and, thus, in highly proliferating tumor cells CDK inhibitors are gaining interest as potential anticancer agents. Clonogenic assay experiments are frequently used to determine drug efficacy against the survival and proliferation of cancer cells. While the anticancer mechanisms of drugs are usually described at the intracellular single-cell level, the experimental measurements are sampled from the entire cancer cell population. This approach may lead to discrepancies between the experimental observations and theoretical explanations of anticipated drug mechanisms. To determine how individual cell responses to drugs that inhibit CDKs affect the growth of cancer cell populations, we developed a spatially explicit hybrid agent-based model. In this model, each cell is equipped with internal cell cycle regulation mechanisms, but it is also able to interact physically with its neighbors. We model cell cycle progression, focusing on the G1 and G2/M cell cycle checkpoints, as well as on related essential components, such as CDK1, CDK2, cell size, and DNA damage. We present detailed studies of how the emergent properties (e.g., cluster formation) of an entire cell population depend on altered physical and physiological parameters. We analyze the effects of CDK1 and CKD2 inhibitors on population growth, time-dependent changes in cell cycle distributions, and the dynamic evolution of spatial cell patterns. We show that cell cycle inhibitors that cause cell arrest at different cell cycle phases are not necessarily synergistically super-additive. Finally, we demonstrate that the physical aspects of cell population growth, such as the formation of tight cell clusters versus dispersed colonies, alter the efficacy of cell cycle inhibitors, both in 2D and 3D simulations. This finding may have implications for interpreting the treatment efficacy results of in vitro experiments, in which treatment is applied before the cells can grow to produce clusters, especially because in vivo tumors, in contrast, form large masses before they are detected and treated.

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Combination of HDAC and topoisomerase inhibitors in small cell lung cancer

Cited by 47 publications

References 40 publications

CRM1 Inhibition Sensitizes Drug Resistant Human Myeloma Cells to Topoisomerase II and Proteasome Inhibitors both In Vitro and Ex Vivo

CRM1 Inhibition Sensitizes Drug Resistant Human Myeloma Cells to Topoisomerase II and Proteasome Inhibitors both In Vitro and Ex Vivo

Vorinostat enhances the cisplatin-mediated anticancer effects in small cell lung cancer cells

The formation of tight tumor clusters affects the efficacy of cell cycle inhibitors: A hybrid model study

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