Benzo[c]phenanthridine alkaloids exhibit strong
anti-proliferative activity in malignant melanoma cells
regardless of their p53 status

J 2011

Benzo[c]phenanthridine alkaloids exhibit strong anti-proliferative activity in malignant melanoma cells regardless of their p53 status

HAMMEROVÁ, Jindřiška, Stjepan ULDRIJAN, Eva TÁBORSKÁ a Iva SLANINOVÁ

Základní údaje

Originální název

Benzo[c]phenanthridine alkaloids exhibit strong anti-proliferative activity in malignant melanoma cells regardless of their p53 status

Autoři

HAMMEROVÁ, Jindřiška (203 Česká republika, domácí), Stjepan ULDRIJAN (203 Česká republika, domácí), Eva TÁBORSKÁ (203 Česká republika, domácí) a Iva SLANINOVÁ (203 Česká republika, garant, domácí)

Vydání

Journal of Dermatological Science, 2011, 0923-1811

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10600 1.6 Biological sciences

Stát vydavatele

Irsko

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 3.718

Kód RIV

RIV/00216224:14110/11:00049782

Organizační jednotka

Lékařská fakulta

DOI

http://dx.doi.org/10.1016/j.jdermsci.2011.01.006

UT WoS

000289495800004

Klíčová slova anglicky

Apoptosis; Benzo[c]phenanthridine; alkaloids; DNA damage; Melanoma p53

Příznaky

Mezinárodní význam

Změněno: 12. 4. 2012 08:31, Mgr. Michal Petr

Anotace

V originále

Background: Search for new substances with antiproliferative activity towards melanoma cells is important since malignant melanoma is notoriously resistant to conventional chemotherapy. Benzo[c]phenanthridine alkaloids (BAs) are natural products with significant anti-proliferative activities, therefore they are considered as agents promising for cancer therapy. Objectives: The effects of five BAs (sanguinarine, chelerythrine, chelidonine, sanguilutine, and chelilutine) on human malignant melanoma cell lines were compared. The study focused on BAs effects on DNA, anti-apoptotic and p53 protein levels; and the involvement of p53 in cellular responses to alkaloids treatment. Methods: Melanoma cell lines, two wild types and two with dysfunctional p53 derived from one of them were used. The mechanism of anti-proliferative and pro-apoptotic effects and the effect on DNA was investigated using MTT assay, flow cytometry, Western blot analysis, fluorescence and electron microscopy. Results: All tested alkaloids exhibit strong anti-proliferative activity. CHL, CHE and SA induced apoptosis, which was probably mediated by decreasing levels of anti-apoptotic proteins (Bcl-xL, Mcl-1, XIAP) and was accompanied by mitochondrial membrane potential decrease as well as caspase-3 and PARP cleavage. Although all alkaloids caused DNA damage, which was demonstrated by induction of H2AX phosphorylation, none of the tested alkaloids stabilised p53 and their toxicity in cells with nonfunctional p53 was comparable to wild type cells. Conclusion: Despite the profound similarity of BAsmolecular structures, it is clear that themechanism of cell death induction is different for each alkaloid. Our results indicate that BAs could be effective in malignant melanoma treatment, including tumours which have lost wild type p53.

Návaznosti

GA525/08/0819, projekt VaV

Název: Rostlinné zdroje minoritních benzofenanthridinových alkaloidů a studium interakcí těchto alkaloidů s DNA

Investor: Grantová agentura ČR, Rostlinné zdroje minoritních benzofenanthridinových alkaloidů a studium interakcí těchto alkaloidů s DNA

LC06077, projekt VaV

Název: Centrum chemické genetiky

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Centrum chemické genetiky

MSM0021622415, záměr

Název: Molekulární podstata buněčných a tkáňových regulací

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Molekulární podstata buněčných a tkáňových regulací

Citovat

HAMMEROVÁ, Jindřiška, Stjepan ULDRIJAN, Eva TÁBORSKÁ a Iva SLANINOVÁ. Benzo[c]phenanthridine alkaloids exhibit strong anti-proliferative activity in malignant melanoma cells regardless of their p53 status. Journal of Dermatological Science. 2011, roč. 62, č. 1, s. 22-35. ISSN 0923-1811. Dostupné z: https://dx.doi.org/10.1016/j.jdermsci.2011.01.006.

@article{937416,
   author = {Hammerová, Jindřiška and Uldrijan, Stjepan and Táborská, Eva and Slaninová, Iva},
   article_number = {1},
   doi = {http://dx.doi.org/10.1016/j.jdermsci.2011.01.006},
   keywords = {Apoptosis; Benzo[c]phenanthridine; alkaloids; DNA damage; Melanoma p53},
   language = {eng},
   issn = {0923-1811},
   journal = {Journal of Dermatological Science},
   title = {Benzo[c]phenanthridine alkaloids exhibit strong anti-proliferative activity in malignant melanoma cells regardless of their p53 status},
   volume = {62},
   year = {2011}
}

TY  - JOUR
ID  - 937416
AU  - Hammerová, Jindřiška - Uldrijan, Stjepan - Táborská, Eva - Slaninová, Iva
PY  - 2011
TI  - Benzo[c]phenanthridine alkaloids exhibit strong anti-proliferative activity in malignant melanoma cells regardless of their p53 status
JF  - Journal of Dermatological Science
VL  - 62
IS  - 1
SP  - 22-35
EP  - 22-35
SN  - 09231811
KW  - Apoptosis
KW  - Benzo[c]phenanthridine
KW  - alkaloids
KW  - DNA damage
KW  - Melanoma p53
N2  - Background: Search for new substances with antiproliferative activity towards melanoma cells is important since malignant melanoma is notoriously resistant to conventional chemotherapy. Benzo[c]phenanthridine alkaloids (BAs) are natural products with significant anti-proliferative activities, therefore they are considered as agents promising for cancer therapy. Objectives: The effects of five BAs (sanguinarine, chelerythrine, chelidonine, sanguilutine, and chelilutine) on human malignant melanoma cell lines were compared. The study focused on BAs effects on DNA, anti-apoptotic and p53 protein levels; and the involvement of p53 in cellular responses to alkaloids treatment. Methods: Melanoma cell lines, two wild types and two with dysfunctional p53 derived from one of them were used. The mechanism of anti-proliferative and pro-apoptotic effects and the effect on DNA was investigated using MTT assay, flow cytometry, Western blot analysis, fluorescence and electron microscopy. Results: All tested alkaloids exhibit strong anti-proliferative activity. CHL, CHE and SA induced apoptosis, which was probably mediated by decreasing levels of anti-apoptotic proteins (Bcl-xL, Mcl-1, XIAP) and was accompanied by mitochondrial membrane potential decrease as well as caspase-3 and PARP cleavage. Although all alkaloids caused DNA damage, which was demonstrated by induction of H2AX phosphorylation, none of the tested alkaloids stabilised p53 and their toxicity in cells with nonfunctional p53 was comparable to wild type cells. Conclusion: Despite the profound similarity of BAsmolecular structures, it is clear that themechanism of cell death induction is different for each alkaloid. Our results indicate that BAs could be effective in malignant melanoma treatment, including tumours which have lost wild type p53.
ER  -

HAMMEROVÁ, Jindřiška, Stjepan ULDRIJAN, Eva TÁBORSKÁ a Iva SLANINOVÁ. Benzo[c]phenanthridine alkaloids exhibit strong anti-proliferative activity in malignant melanoma cells regardless of their p53 status. \textit{Journal of Dermatological Science}. 2011, roč.~62, č.~1, s.~22-35. ISSN~0923-1811. Dostupné z: https://dx.doi.org/10.1016/j.jdermsci.2011.01.006.

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