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Synthesis and biological evaluation of N-biphenyl-nicotinic based moiety compounds: A new class of antimitotic agents for the treatment of Hodgkin Lymphoma
- Source :
- Cancer letters. 445
- Publication Year :
- 2018
-
Abstract
- We previously demonstrated that some N-biphenylanilides caused cell-cycle arrest at G2/M transition in breast cancer cells. Among them we choose three derivatives, namely PTA34, PTA73 and RS35 for experimentation in solid tumor cell lines, classical Hodgkin Lymphoma (cHL) cell lines and bona fide normal cell lines. Almost all tumor cells were sensitive to compounds in the nanomolar range whereas, they were not cytotoxic to normal ones. Interestingly the compounds caused a strong G2/M phase arrest in cHL cell lines, thus, here we investigated whether they affected the integrity of microtubules in such cells. We found that they induced a long prometaphase arrest, followed by induction of apoptosis which involved mitochondria. PTA73 and RS35 induced the mitotic arrest through the fragmentation of microtubules which prevented the kinethocore-mitotic spindle interaction and the exit from mitosis. PTA34 is instead a tubulin-targeting agent because it inhibited the tubulin polymerization as vinblastine. As such, PTA34 maintained the Cyclin B1-CDK1 regulatory complex activated during the G2/M arrest while inducing the inactivation of Bcl-2 through phosphorylation in Ser70, the degradation of Mcl-1 and a strong activation of BIML and BIMS proapoptotic isoforms. In addition PTA34 exerted an antiangiogenic effect by suppressing microvascular formation.
- Subjects :
- 0301 basic medicine
Cancer Research
Nicotine
Prometaphase
Cell Survival
Antimitotic Agents
03 medical and health sciences
0302 clinical medicine
Cell Line, Tumor
CDC2 Protein Kinase
medicine
Cytotoxic T cell
Humans
Fragmentation (cell biology)
Cyclin B1
Mitosis
Cell Proliferation
Membrane Potential, Mitochondrial
Molecular Structure
Chemistry
Biphenyl Compounds
Hodgkin Disease
Vinblastine
Cell biology
Mitochondria
Gene Expression Regulation, Neoplastic
030104 developmental biology
Oncology
Apoptosis
Cell culture
030220 oncology & carcinogenesis
Antimitotic Agent
medicine.drug
Subjects
Details
- ISSN :
- 18727980
- Volume :
- 445
- Database :
- OpenAIRE
- Journal :
- Cancer letters
- Accession number :
- edsair.doi.dedup.....9c38929a37dec7a549aa8927869263ae