G‐Quadruplex‐Binding Small Molecule Induces Synthetic Lethality in Breast Cancer Cells by Inhibiting c‐MYC and BCL2 Expression

ChemBioChem ◽  
2020 ◽  
Vol 21 (7) ◽  
pp. 963-970 ◽  
Author(s):  
Rakesh Paul ◽  
Tania Das ◽  
Manish Debnath ◽  
Ajay Chauhan ◽  
Jyotirmayee Dash
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Small Molecule ◽  
Breast Cancer Cells ◽  
Synthetic Lethality ◽  
G Quadruplex ◽  
Bcl2 Expression

scholarly journals Mutant p53L194F Harboring Luminal-A Breast Cancer Cells Are Refractory to Apoptosis and Cell Cycle Arrest in Response to MortaparibPlus, a Multimodal Small Molecule Inhibitor

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3043
Author(s):  
Ahmed Elwakeel ◽  
Anissa Nofita Sari ◽  
Jaspreet Kaur Dhanjal ◽  
Hazna Noor Meidinna ◽  
Durai Sundar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Small Molecule ◽  
Breast Cancer Cells ◽  
Luminal A ◽  
Molecular Analyses ◽  
Cycle Arrest ◽  
Mcf 7

We previously performed a drug screening to identify a potential inhibitor of mortalin–p53 interaction. In four rounds of screenings based on the shift in mortalin immunostaining pattern from perinuclear to pan-cytoplasmic and nuclear enrichment of p53, we had identified MortaparibPlus (4-[(1E)-2-(2-phenylindol-3-yl)-1-azavinyl]-1,2,4-triazole) as a novel synthetic small molecule. In order to validate its activity and mechanism of action, we recruited Luminal-A breast cancer cells, MCF-7 (p53wild type) and T47D (p53L194F) and performed extensive biochemical and immunocytochemical analyses. Molecular analyses revealed that MortaparibPlus is capable of abrogating mortalin–p53 interaction in both MCF-7 and T47D cells. Intriguingly, upregulation of transcriptional activation function of p53 (as marked by upregulation of the p53 effector gene—p21WAF1—responsible for cell cycle arrest and apoptosis) was recorded only in MortaparibPlus-treated MCF-7 cells. On the other hand, MortaparibPlus-treated T47D cells exhibited hyperactivation of PARP1 (accumulation of PAR polymer and decrease in ATP levels) as a possible non-p53 tumor suppression program. However, these cells did not show full signs of either apoptosis or PAR-Thanatos. Molecular analyses attributed such a response to the inability of MortaparibPlus to disrupt the AIF–mortalin complexes; hence, AIF did not translocate to the nucleus to induce chromatinolysis and DNA degradation. These data suggested that the cancer cells possessing enriched levels of such complexes may not respond to MortaparibPlus. Taken together, we report the multimodal anticancer potential of MortaparibPlus that warrants further attention in laboratory and clinical studies.

scholarly journals Androstano-arylpyrimidines: Novel small molecule inhibitors of MDR1 for sensitizing multidrug-resistant breast cancer cells

2021 ◽  
Vol 156 ◽  
pp. 105587
Author(s):  
Mohana Krishna Gopisetty ◽  
Dóra Izabella Adamecz ◽  
Ferenc István Nagy ◽  
Ádám Baji ◽  
Vasiliki Lathira ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Small Molecule ◽  
Breast Cancer Cells ◽  
Small Molecule Inhibitors ◽  
Multidrug Resistant

scholarly journals Screening antiproliferative drug for breast cancer from bisbenzylisoquinoline alkaloid tetrandrine and fangchinoline derivatives by targeting BLM helicase

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Wangming Zhang ◽  
Shuang Yang ◽  
Jinhe Liu ◽  
Linchun Bao ◽  
He Lu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Binding ◽  
Small Molecules ◽  
Cancer Cells ◽  
Small Molecule ◽  
Breast Cancer Cells ◽  
Dna Unwinding ◽  
Protein Levels ◽  
Blm Helicase ◽  
Bisbenzylisoquinoline Alkaloids

Abstract Background The high expression of BLM (Bloom syndrome) helicase in tumors involves its strong association with cell expansion. Bisbenzylisoquinoline alkaloids own an antitumor property and have developed as candidates for anticancer drugs. This paper aimed to screen potential antiproliferative small molecules from 12 small molecules (the derivatives of bisbenzylisoquinoline alkaloids tetrandrine and fangchinoline) by targeting BLM642–1290 helicase. Then we explore the inhibitory mechanism of those small molecules on proliferation of MDA-MB-435 breast cancer cells. Methods Fluorescence polarization technique was used to screen small molecules which inhibited the DNA binding and unwinding of BLM642–1290 helicase. The effects of positive small molecules on the ATPase and conformation of BLM642–1290 helicase were studied by the malachite green-phosphate ammonium molybdate colorimetry and ultraviolet spectral scanning, respectively. The effects of positive small molecules on growth of MDA-MB-435 cells were studied by MTT method, colony formation and cell counting method. The mRNA and protein levels of BLM helicase in the MDA-MB-435 cells after positive small molecule treatments were examined by RT-PCR and ELISA, respectively. Results The compound HJNO (a tetrandrine derivative) was screened out which inhibited the DNA binding, unwinding and ATPase of BLM642–1290 helicase. That HJNO could bind BLM642–1290helicase to change its conformationcontribute to inhibiting the DNA binding, ATPase and DNA unwinding of BLM642–1290 helicase. In addition, HJNO showed its inhibiting the growth of MDA-MB-435 cells. The values of IC50 after drug treatments for 24 h, 48 h and 72 h were 19.9 μmol/L, 4.1 μmol/L and 10.9 μmol/L, respectively. The mRNA and protein levels of BLM helicase in MDA-MB-435 cells increased after HJNO treatment. Those showed a significant difference (P < 0.05) compared with negative control when the concentrations of HJNO were 5 μmol/L and 10 μmol/L, which might contribute to HJNO inhibiting the DNA binding, ATPase and DNA unwinding of BLM helicase. Conclusion The small molecule HJNO was screened out by targeting BLM642–1290 helicase. And it showed an inhibition on MDA-MB-435 breast cancer cells expansion.

Abstract LB-A16: Novel Small Molecule ONC201 Induces Cell Death in Triple Negative and Non-triple Negative Breast Cancer Cells

2015 ◽  
Author(s):  
Marie D. Baumeister ◽  
Jessica Wagner ◽  
Christina L.B. Kline ◽  
Joshua E. Allen ◽  
David T. Dicker ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Small Molecule ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative
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