Mitotic catastrophe and cancer drug resistance: A link that must to be broken

Denisenko, Tatiana V.; Сорокина, И. В.; Gogvadze, Vladimir; Zhivotovsky, Boris

doi:10.1016/j.drup.2015.11.002

Cited by 87 publications

(95 citation statements)

References 119 publications

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“…Polyploidy is linked to increased genomic instability and the induction of tumor heterogeneity and ultimately drug resistance. [22][23][24][25] In this study we have determined that the G2/M arrest we previously reported in HDACi-sensitive DLBCL cell lines is due to accumulation of cells in early mitosis, consistent with SAC activation. In contrast, the HDACi belinostat delays mitotic progression but does not prevent mitotic completion in HDACi-resistant DLBCL cell lines.…”

Section: Introductionsupporting

confidence: 75%

“…In the prolonged presence of vincristine, a fraction of SUDHL8 cells slip out of mitosis in a tetraploid state and progress through the cell cycle yielding a population of cells that have 8N DNA content, including some that have entered mitosis. Interestingly, the induction of polyploidy by inhibitors of mitosis is associated with drug resistance, 23,46 and it has been proposed that the continued survival of polyploid cells may give rise to aneuploidy that promotes cancer progression. 46,[53][54][55][56] Deng et al measured vincristine sensitivity in DLBCL cell lines and found that SUDHL8 cells were relatively resistant while SUDHL4 cells were much more sensitive.…”

Section: Discussionmentioning

confidence: 99%

“…8A). Mitotic slippage without genome division has been documented to occur with other drugs that target mitosis and may be associated with drug resistance and the development of aneuploidy [reviewed in 23,[44][45][46] ]. Interestingly, the presence of belinostat largely prevents the vincristine-induced accumulation of polyploid SUDHL8 cells (Fig.…”

Section: Belinostat Prevents Vincristine-induced Formation Of Polyplomentioning

confidence: 99%

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Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma

Havas

Rodrigues

Bhakta

et al. 2016

Cancer Biology & Therapy

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Diffuse Large B-cell lymphoma (DLBCL) is an aggressive malignancy that has a 60 percent 5-year survival rate, highlighting a need for new therapeutic approaches. Histone deacetylase inhibitors (HDACi) are novel therapeutics being clinically-evaluated in combination with a variety of other drugs. However, rational selection of companion therapeutics for HDACi is difficult due to their poorly-understood, celltype specific mechanisms of action. To address this, we developed a pre-clinical model system of sensitivity and resistance to the HDACi belinostat using DLBCL cell lines. In the current study, we demonstrate that cell lines sensitive to the cytotoxic effects of HDACi undergo early mitotic arrest prior to apoptosis. In contrast, HDACi-resistant cell lines complete mitosis after a short delay and arrest in G1. To force mitotic arrest in HDACi-resistant cell lines, we used low dose vincristine or paclitaxel in combination with belinostat and observed synergistic cytotoxicity. Belinostat curtails vincristine-induced mitotic arrest and triggers a strong apoptotic response associated with downregulated MCL-1 expression and upregulated BIM expression. Resistance to microtubule targeting agents (MTAs) has been associated with their propensity to induce polyploidy and thereby increase the probability of genomic instability that enables cancer progression. Co-treatment with belinostat effectively eliminated a vincristine-induced, actively cycling polyploid cell population. Our study demonstrates that vincristine sensitizes DLBCL cells to the cytotoxic effects of belinostat and that belinostat prevents polyploidy that could cause vincristine resistance. Our findings provide a rationale for using low dose MTAs in conjunction with HDACi as a potential therapeutic strategy for treatment of aggressive DLBCL.

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Section: Introductionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Belinostat Prevents Vincristine-induced Formation Of Polyplomentioning

confidence: 99%

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Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma

Havas

Rodrigues

Bhakta

et al. 2016

Cancer Biology & Therapy

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“…Previous clinical studies have focused on Chinese medicine preparations based on anti-proliferative effects, while in recent years the focus has shifted to the development of preparations which can induce differentiation and apoptosis of cancer cells (9,10). Drugs that induce apoptosis can selectively target cancer cells and therefore normal cells are unaffected by treatment (9).…”

Section: Introductionmentioning

confidence: 99%

“…A number of active chemical substances in natural plants have strong apoptotic-inducing effects on cancer cells (8)(9)(10), and studies have demonstrated that lentinan and oridonin are active substances with cancer cell apoptosis-inducing effects (3,8).…”

Section: Introductionmentioning

confidence: 99%

Oridonin increases anticancer effects of lentinan in HepG2 human hepatoblastoma cells

Sun¹,

Han

Duan

et al. 2017

Oncol Lett

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Abstract. The aim of the present study was to investigate whether oridonin is able to increase the effects of lentinan (LNT) in HepG2 human hepatoblastoma cells by MTT, flow cytometry, reverse transcription-quantitative polymerase chain reaction and western blot analysis. The in vitro results demonstrated that 20 µg/ml of oridonin was a nontoxic concentration for L02 normal liver cells and HepG2 liver cancer cells. Furthermore, treatment with 0-200 µg/ml LNT was only able to decrease the viability of HepG2 liver cancer cells. The growth inhibitory rate of the LNT-L (100 µg/ml) treatment group was 20.7% and the rate of the LNT-H (200 µg/ml) treatment group was 54.8%. Notably, the growth inhibitory rate of the oridonin + LNT-H group was 84.3%. The highest percentage of apoptotic cells was observed in the oridonin + LNT-H group (20 µg/ml oridonin and 200 µg/ml LNT). The percentage of apoptotic cells in the oridonin + LNT-H group was significantly different from the percentage of apoptotic cells in the LNT-H (26.1%) and the LNT-L (16.8%) groups. Treatment with LNT produced an increase in caspase-3, caspase-9, Bcl-2-like protein 4, p53, p21, nuclear factor κB inhibitor-α mRNA and protein expression and a decrease in B-cell lymphoma 2 and nuclear factor-κB expression in HepG2 cells compared with untreated control cells. Treatment with a combination of oridonin and LNT-H induced a further increase in expression with the biggest differences in expression observed between the oridonin + LNT-H group and control. It was observed that treatment with oridonin was able to increase the anticancer effects of LNT in HepG2 cells. Therefore, oridonin may be used to sensitize cells to LNT.

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Plants from Northwestern Anatolia Display Selective Cytotoxicity and Induce Mitotic Catastrophe: A Study on Anticancer and Genotoxic Activities

Sarimahmut

Çelikler

2023

Chemistry & Biodiversity

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Anatolia is rich in floristic diversity with a high rate of endemism. Eight plant species from northwestern Anatolia were evaluated for their anti‐growth properties in two malignant (MCF‐7 and MDA‐MB‐231) and a non‐malignant (MCF‐10A) breast cell line. The two most active extracts, Achillea multifida (AME) and Astragalus sibthorpianus (ASE), induced apoptotic cell death in all cell lines. The major phenolic compounds in AME were identified as chlorogenic acid, and catechins in ASE. ASE displayed selective cytotoxicity against breast cancer cells, with DNA damage repair in non‐malignant cells contributing to its selectivity. Conversely, AME induced DNA damage in a time‐dependent manner and displayed a dual dose‐dependent biological activity, resulting in mitotic catastrophe and apoptosis at different doses. Most plant species exhibited moderate to strong cytotoxicity, highlighting their medicinal and economic potential and the need for their protection.

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Mitotic catastrophe and cancer drug resistance: A link that must to be broken

Cited by 87 publications

References 119 publications

Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma

Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma

Oridonin increases anticancer effects of lentinan in HepG2 human hepatoblastoma cells

Plants from Northwestern Anatolia Display Selective Cytotoxicity and Induce Mitotic Catastrophe: A Study on Anticancer and Genotoxic Activities

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