scholarly journals Mdivi-1 induces spindle abnormalities and augments taxol cytotoxicity in MDA-MB-231 cells

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Chieh-Ting Fang ◽  
Hsiao-Hui Kuo ◽  
Chia-Jung Yuan ◽  
Jhong-Syuan Yao ◽  
Ling-Huei Yih
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Mitochondrial Fission ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Tubulin Polymerization ◽  
Breast Cancer Patients ◽  
Antimitotic Activity ◽  
Tnbc Cell Line ◽  
Taxol Resistance

AbstractTaxol is a first-line chemotherapeutic for numerous cancers, including the highly refractory triple-negative breast cancer (TNBC). However, it is often associated with toxic side effects and chemoresistance in breast cancer patients, which greatly limits the clinical utility of the drug. Hence, compounds that act in concert with taxol to promote cytotoxicity may be useful to improve the efficacy of taxol-based chemotherapy. In this study, we demonstrated that mdivi-1, a putative inhibitor of mitochondrial fission protein Drp1, enhances the anticancer effects of taxol and overcomes taxol resistance in a TNBC cell line (MDA-MB-231). Not only did mdivi-1 induce mitotic spindle abnormalities and mitotic arrest when used alone, but it also enhanced taxol-induced antimitotic effects when applied in combination. In addition, mdivi-1 induced pronounced spindle abnormalities and cytotoxicity in a taxol-resistant cell line, indicating that it can overcome taxol resistance. Notably, the antimitotic effects of mdivi-1 were not accompanied by prominent morphological or functional alterations in mitochondria and were Drp1-independent. Instead, mdivi-1 exhibited affinity to tubulin at μM level, inhibited tubulin polymerization, and immediately disrupted spindle assembly when cells entered mitosis. Together, our results show that mdivi-1 associates with tubulin and impedes tubulin polymerization, actions which may underlie its antimitotic activity and its ability to enhance taxol cytotoxicity and overcome taxol resistance in MDA-MB-231 cells. Furthermore, our data imply a possibility that mdivi-1 could be useful to improve the therapeutic efficacy of taxol in breast cancer.

scholarly journals YES1 as a Therapeutic Target for HER2-Positive Breast Cancer after Trastuzumab and Trastuzumab-Emtansine (T-DM1) Resistance Development

2021 ◽  
Vol 22 (23) ◽  
pp. 12809
Author(s):  
Miwa Fujihara ◽  
Tadahiko Shien ◽  
Kazuhiko Shien ◽  
Ken Suzawa ◽  
Tatsuaki Takeda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Resistance Mechanisms ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Trastuzumab Emtansine ◽  
Her2 Positive

Trastuzumab-emtansine (T-DM1) is a therapeutic agent molecularly targeting human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), and it is especially effective for MBC with resistance to trastuzumab. Although several reports have described T-DM1 resistance, few have examined the mechanism underlying T-DM1 resistance after the development of acquired resistance to trastuzumab. We previously reported that YES1, a member of the Src family, plays an important role in acquired resistance to trastuzumab in HER2-amplified breast cancer cells. We newly established a trastuzumab/T-DM1-dual-resistant cell line and analyzed the resistance mechanisms in this cell line. At first, the T-DM1 effectively inhibited the YES1-amplified trastuzumab-resistant cell line, but resistance to T-DM1 gradually developed. YES1 amplification was further enhanced after acquired resistance to T-DM1 became apparent, and the knockdown of the YES1 or the administration of the Src inhibitor dasatinib restored sensitivity to T-DM1. Our results indicate that YES1 is also strongly associated with T-DM1 resistance after the development of acquired resistance to trastuzumab, and the continuous inhibition of YES1 is important for overcoming resistance to T-DM1.

scholarly journals DNA N6-Methyladenine (6mA) Modification Regulates Drug Resistance in Triple Negative Breast Cancer

2021 ◽  
Vol 10 ◽  
Author(s):  
Xianneng Sheng ◽  
Jinqiu Wang ◽  
Yu Guo ◽  
Jiabo Zhang ◽  
Jin Luo
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cell Line ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Biological Marker ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Expression Level ◽  
Normal Tissues

Triple negative breast cancer (TNBC) is a subtype of breast cancer with strong aggressiveness and poor clinical treatment effect, accounting for about 10–20% of breast cancer cases. N(6)-methyldeoxyadenosine (6mA) is the most conservative DNA modification in prokaryotes and eukaryotes. It is widely found in bacteria and has such functions as DNA mismatch repair, chromosome separation and virulence regulation. We determined that 6mA was modified in TNBC cell line MDA-MB-231 and the TNBC tissue. Meanwhile, compared with normal tissues, the expression level of 6mA and its methylase N6AMT1 was significantly decreased in TNBC tissue. MDA-MB-231cells were cultured with 8μM Olaparib for 2 months to construct drug-resistant cell line 231-RO. It was found that the level of 6mA also increased significantly, and the expression of N6AMT1 or ALKBH1 could effectively influence the drug resistance. Subsequently, we found that LINP1 was highly expressed in 231-RO, which was involved in DNA repair, and the expression of LINP1 could be positively regulated by 6mA modification. LINP1 expression level is directly related to TNBC drug resistance. The above results indicate that 6mA may be a new biological marker of TNBC. Meanwhile, 6mA modification may be involved in the regulation of Olaparib resistance.

scholarly journals Genomic Adaption and Mutational Patterns in a HaCaT Subline Resistant to Alkylating Agents and Ionizing Radiation

2021 ◽  
Vol 22 (3) ◽  
pp. 1146
Author(s):  
Reinhard Ullmann ◽  
Benjamin Valentin Becker ◽  
Simone Rothmiller ◽  
Annette Schmidt ◽  
Horst Thiermann ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Line ◽  
Copy Number ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Chromosomal Translocations ◽  
Dna Copy Number ◽  
Mutational Signatures ◽  
Copy Number Changes ◽  
And Oxidative Stress

Sulfur mustard (SM) is a chemical warfare agent that can damage DNA via alkylation and oxidative stress. Because of its genotoxicity, SM is cancerogenic and the progenitor of many chemotherapeutics. Previously, we developed an SM-resistant cell line via chronic exposure of the popular keratinocyte cell line HaCaT to increasing doses of SM over a period of 40 months. In this study, we compared the genomic landscape of the SM-resistant cell line HaCaT/SM to its sensitive parental line HaCaT in order to gain insights into genetic changes associated with continuous alkylation and oxidative stress. We established chromosome numbers by cytogenetics, analyzed DNA copy number changes by means of array Comparative Genomic Hybridization (array CGH), employed the genome-wide chromosome conformation capture technique Hi-C to detect chromosomal translocations, and derived mutational signatures by whole-genome sequencing. We observed that chronic SM exposure eliminated the initially prevailing hypotetraploid cell population in favor of a hyperdiploid one, which contrasts with previous observations that link polyploidization to increased tolerance and adaptability toward genotoxic stress. Furthermore, we observed an accumulation of chromosomal translocations, frequently flanked by DNA copy number changes, which indicates a high rate of DNA double-strand breaks and their misrepair. HaCaT/SM-specific single-nucleotide variants showed enrichment of C > A and T > A transversions and a lower rate of deaminated cytosines in the CpG dinucleotide context. Given the frequent use of HaCaT in toxicology, this study provides a valuable data source with respect to the original genotype of HaCaT and the mutational signatures associated with chronic alkylation and oxidative stress.

Platinum pyridinecarboxaldimine complexes containing boronate esters

2004 ◽  
Vol 82 (12) ◽  
pp. 1692-1699 ◽  
Author(s):  
Hanni A Darwish ◽  
Stephen J Scales ◽  
Jennifer L Horton ◽  
Liliya G Nikolcheva ◽  
Haiwen Zhang ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Key Words ◽  
Cell Line ◽  
Platinum Complexes ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Boronate Esters ◽  
Human Ovarian Carcinoma

Condensation of 2-pyridinecarboxaldehydes with 2-, 3-, and 4-H2NC6H4Bpin (pin = 1,2-O2C2Me4) gave the corresponding boron-containing pyridinecarboxaldimines (N–NBpin). Addition of these ligands to [PtCl2(coe)]2 (coe = cis-cyclooctene) gave complexes of the type cis-PtCl2(N–NBpin) in moderate yields. The platinum complexes have been examined for their potential cytotoxicities against OV2008 (human ovarian carcinoma) and the analogous cisplatin-resistant cell line C13. Key words: boronate esters, pyridinecarboxaldimines, cytotoxicity, platinum, boron.

An immortalized drug-resistant cell line established from 12–13-day mouse embryos for the propagation of human embryonic stem cells

2006 ◽  
Vol 74 (4) ◽  
pp. 160-166 ◽  
Author(s):  
Shiro Iuchi ◽  
Meytha Marsch-Moreno ◽  
Cristina Velez-DelValle ◽  
Karen Easley ◽  
Walid Kuri-Harcuch ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Cell Line ◽  
Human Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Mouse Embryos ◽  
Drug Resistant ◽  
Drug Resistant Cell

scholarly journals Genotoxic Effects of Green Tea Extract on Human Laryngeal Carcinoma Cells In Vitro

2011 ◽  
Vol 62 (2) ◽  
pp. 139-146 ◽  
Author(s):  
Ksenija Durgo ◽  
Sandra Kostić ◽  
Katarina Gradiški ◽  
Draženka Komes ◽  
Maja Osmak ◽  
...  
Keyword(s):  
Cell Line ◽  
Green Tea ◽  
Laryngeal Carcinoma ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Green Tea Extract ◽  
Carcinoma Cells ◽  
Tea Extract ◽  
Human Laryngeal Carcinoma

Genotoxic Effects of Green Tea Extract on Human Laryngeal Carcinoma Cells In VitroGreen tea (Camellia sinensis) contains several bioactive compounds which protect the cell and prevent tumour development. Phytochemicals in green tea extract (mostly flavonoids) scavenge free radicals, but also induce pro-oxidative reactions in the cell. In this study, we evaluated the potential cytotoxic and prooxidative effects of green tea extract and its two main flavonoid constituents epigallocatechin gallate (EGCG) and epicatechin gallate (ECG) on human laryngeal carcinoma cell line (HEp2) and its cross-resistant cell line CK2. The aim was to see if the extract and its two flavonoids could increase the sensitivity of the cisplatin-resistant cell line CK2 in comparison to the parental cell line. The results show that EGCG and green tea extract increased the DNA damage in the CK2 cell line during short exposure. The cytotoxicity of EGCG and ECG increased with the time of incubation. Green tea extract induced lipid peroxidation in the CK2 cell line. The pro-oxidant effect of green tea was determined at concentrations higher than those found in traditionally prepared green tea infusions.

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