Rintasyöpä, polyamiiniaineenvaihdunnan osuus , roscovitine

On havaittu polyaminipitoisuuuden vaikuttavan rintasyöpäsolun apoptoosin valiutumiseen mitokondriaväliteistä apoptoosia tutkittaessa.

LÄHDE:  Arisan ED¹, Obakan P, Coker A, Palavan-Unsal N.

Inhibition of ornithine decarboxylase alters the roscovitine-induced mitochondrial-mediated apoptosis in MCF-7 breast cancer cells

.Mol Med Rep. 2012 May;5(5):1323-9. doi: 10.3892/mmr.2012.786. Epub 2012 Feb 13.

TIIVISTELMÄ, suomennosta.
 Polyaminit ovat pieniä alifaattisia amineja, joilla on  tuntuva osa multisellulaarisissa funktioissa.  Polyaminipitoisuuksia kontrolloi entsyymi ODC, ornitiinidekarboksylaasi.
 joka rajoittaa polyaminien biosynteesitahtia,
DFMO molekyyli, alfa-difluorometyyli-ornitiini, on  mainitun ODC- entsyymin estäjä ja sillä  on havaittu  antiproliferatiivista vaikutusta ihmisen syövässä, koska se estää ODC entsyymin  palautumattomasti, iorreversibelisti.  ODC entsyymin on  havaittu ilmenevän  rintasyövässä  ylimäärin.

Abstract

Polyamines (PAs) are small aliphatic amines that play a major role in multicellular functions. The PA levels are controlled by ornithine decarboxylase (ODC),
 the rate limiting enzyme of PA biosynthesis.  α-difluoromethylornithine (DFMO) is the ODC inhibitor, which has been shown to act as an antiproliferative agent in human cancer cells by irreversibly inhibiting ODC, which is overexpressed in breast cancer cells. 

• Roskovitiini (ROSC) on taas  selektiivinen sykliinistä riippuvainen kinaasin estäjä , joka pystyy indusoimaan  solusyklin pysähtymän ja  siitä seuraavan apotoitumisen  tuumorisolussa . Tässä tutkimuksessa  tutkijat  halusivat tutkia sitä mahdollista osuutta, mikä polyamineilla saattaisi olla  ROSC- indusoituun apoptoosiin estrogeenistä riippuvissa MCP-7 rintasyöpäsoluissa.

Roscovitine (ROSC; CYC202), a selective cyclin-dependent kinase inhibitor, induces cell cycle arrest and concomitantly apoptosis in tumor cells. In this study, we aimed to investigate the possible role of PAs in ROSC-induced apoptosis in estrogen-dependent MCF-7 breast cancer cells. Cell viability was assessed following the exposure of MCF-7 cells to DFMO and/or ROSC by MTT cell viability assay. 

•  Lääkkeen indusoimaa apoptoosia arvioitiin  solukuoleman aiheuttamaa DNA. fragmentaatiota  selvittävällä menetelmällä. Määritettiin myös mitokondriakalvon potentiaalin  poistuminen, kaspaasi- 9 ja PARP pilkkoutuma, jotta   saataisiin selville mitokondriaalisen apoptoosin osuus. Myös arvioitiin Bcl-2 perheen  modulaatio  immunologisella tekniikalla . Lääkkeen aiheuttama reaktiivisten happilajien (ROS) muodostus määritettiin.  

To evaluate the drug-induced apoptotic events, DNA fragmentation by Cell Death ELISA assay and 4,6-diamidino-2-phenylindole staining, were utilized. The disruption of mitochondrial membrane potential, caspase-9 and PARP cleavage was also determined in order to investigate the role of mitochondrial-mediated apoptosis. The modulation of Bcl-2 family members was also evaluated using the immunoblotting technique. Drug-induced reactive oxygen species was determined by a fluorometer following 2',7'-dichlorofluorescein diacetate staining. 

•  Tutkijat totesivat  ROSC:in  indusoivan   apoptoosia   annoksesta ja kaspaasista riippuvalla tavalla. ODC- spesifinen inhibiittori DFMO  muunsi ROSC:in apoptoottisia vaikutuksia vähentämällä reaktiivisten happilajien kehittymistä, vähentämällä solunsisäistä polyaminiallasta ja moduloimalla pro-apoptoottisia ja antiapoptoottisia Bcl-2 perheen jäseniä. Kaikki nämä löydöt viittasivat siihen, että ODC entsyymi saattaisi olla kriittinen kohde polyaminien metabolisen tien arvioinnissa terapeuttisena kohteena ROSC:in indusoimassa mitokondriaalisesti välittyvässä  apoptoosissa niissä rintasyöpäsoluissa, jotka ovat estrogeenistä riippuvia MCF-7 soluja.

We found that ROSC induced apoptosis in a dose- and caspase-dependent manner. The ODC specific inhibitor, DFMO, altered the apoptotic effects of ROSC by increasing the generation of reactive oxygen species, decreasing the PA intracellular pool and modulating pro-apoptotic and anti-apoptotic Bcl-2 family members. All these findings suggest that ODC may be a critical target for evaluating the PA metabolic pathway as a therapeutic target in ROSC-induced mitochondrial-mediated apoptosis in estrogen-dependent MCF-7 breast cancer cells.

PMID:

22344475

[PubMed - indexed for MEDLINE]

• MIKÄ MOLEKYYLI on roscovitine? Onko se jo käytössä? Wikipepdia kertoo:
• Seliciclib (roscovitine or CYC202) is an experimental drug candidate in the family of pharmacological cyclin-dependent kinase (CDK) inhibitors that preferentially inhibit multiple enzyme targets including CDK2, CDK7 and CDK9, which alter the growth phase or state within the cell cycle of treated cells. Seliciclib is being developed by Cyclacel.
  Seliciclib is being researched for the treatment of non-small cell lung cancer (NSCLC), Cushing's Disease, leukemia, HIV infection, herpes simplex infection, cystic fibrosis^[1] and the mechanisms of chronic inflammation disorders.
  Seliciclib is a 2,6,9-substituted purine analog. Its structure in complex with CDK2 was determined in 1996.^[2] Seliciclib inhibits CDK2/E, CDK2/A, CDK7 and CDK9.^[3]

•  Uusinta tietoa tästä  atufagosytointi/apoptoosi - vaihteen valiutumisesta mahdollisesrti polyaminiaineenvaihdunnan avulla.

Arisan ED1, Akkoç Y1, Akyüz KG1, Kerman EM1, Obakan P1, Çoker-Gürkan A1, Ünsal NP1. 
Rep. 2015 Feb 4. doi: 10.3892/mmr.2015.3303. [Epub ahead of print]
 Polyamines modulate the roscovitine-induced cell death switch decision autophagy vs. apoptosis in MCF-7 and MDA-MB-231 breast cancer cells.


 Abstract
 Current clinical strategies against breast cancer mainly involve the use of anti‑hormonal agents to decrease estrogen production; however, development of resistance is a major problem.
 The resistance phenotype depends on the modulation of cell‑cycle regulatory proteins, cyclins and cyclin‑dependent kinases. Roscovitine, a selective inhibitor of cyclin‑dependent kinases, shows high therapeutic potential by causing cell‑cycle arrest in various cancer types.

 Autophagy is a type of cell death characterized by the enzymatic degradation of macromolecules and organelles in double‑ or multi‑membrane autophagic vesicles. This process has important physiological functions, including the degradation of misfolded proteins and organelle turnover.

Recently, the switch between autophagy and apoptosis has been proposed to constitute an important regulator of cell death in response to chemotherapeutic drugs. The process is regulated by several proteins, such as the proteins of the Atg family, essential for the initial formation of the autophagosome, and PI3K, important at the early stages of autophagic vesicle formation.

Polyamines (PAs) are small aliphatic amines that play major roles in a number of eukaryotic processes, including cell proliferation. The PA levels are regulated by ornithine decarboxylase (ODC), the rate‑limiting enzyme in PA biosynthesis.

 In this study, we aimed to investigate the role of PAs in roscovitine‑induced autophagic/apoptotic cell death in estrogen receptor‑positive MCF‑7 and estrogen receptor‑negative MDA‑MB‑231 breast cancer cells. 

 We show that MDA‑MB‑231 cells are more resistant to roscovitine than MCF‑7 cells. This difference was related to the regulation of autophagic key molecules in MDA‑MB‑231 cells.
In addition, we found that exogenous PAs have a role in the cell death decision between roscovitine‑induced apoptosis or autophagy in MCF‑7 and MDA‑MB‑231 breast cancer cells. PMID: 25650699 [PubMed - as supplied by publisher]