A novel quinone-based derivative (DTNQ-Pro) induces apoptotic death via modulation of heat shock protein expression in Caco-2 cells.
OBJECTIVE
The resistance of human colon adenocarcinoma cells to antineoplastic agents may be related to the high endogenous expression of stress proteins, including the family of heat shock proteins (HSPs). Recently, a quinone-based pentacyclic derivative, DTNQ-Pro, showed high cytotoxic activity in human colon carcinoma cell lines. The aim of the present study was to determine the precise cellular mechanisms of this cytotoxic action of DTNQ-Pro.


METHODS
Using human colorectal carcinoma-derived Caco-2 cells as a model, we studied the effects of DTNQ-Pro on cellular viability and oxidative stress; HSP70 and HSP27 accumulation; and cell cycle, differentiation and apoptosis.


RESULTS
Incubation of Caco-2 cells with DTNQ-Pro reduced cell growth and increased the levels of reactive oxygen species in mitochondria. After 48 h of treatment, cells surviving showed an increased expression of Mn-superoxide dismutase (SOD), nitric oxide production and membrane lipid peroxidation. Treatment with DTNQ-Pro decreased HSP70 expression, and redistributed HSP27 and vimentin within the cell. DTNQ-Pro down-regulated the expression of A and B cyclins with arrest of the cell cycle in S phase and increased cellular differentiation. A second treatment of Caco-2 cells with DTNQ-Pro induced cellular death by activation of the apoptotic pathway.


CONCLUSIONS
DTNQ-Pro causes Caco-2 cell death by induction of apoptosis via inhibition of HSP70 accumulation and the intracellular redistribution of HSP27. These findings suggest the potential use of DTNQ-Pro in combination chemotherapy for colon cancer.
Gomez-Monterrey
Isabel
I
Department of Pharmaceutical and Toxicological Chemistry, University of Naples Federico II, Naples, Italy.
Campiglia
Pietro
P
Bertamino
Alessia
A
Aquino
Claudio
C
Sala
Marina
M
Grieco
Paolo
P
Dicitore
Alessandra
A
Vanacore
Daniela
D
Porta
Amalia
A
Maresca
Bruno
B
Novellino
Ettore
E
Stiuso
Paola
P
D000230:Adenocarcinoma / Q000188:drug therapy*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D015536:Down-Regulation / Q000187:drug effects*; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018832:Molecular Chaperones; D009994:Osmolar Concentration; D018384:Oxidative Stress / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D011809:Quinones / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D013141:Spiro Compounds / Q000494:pharmacology*; D014746:Vimentin / Q000378:metabolism
C553169:(3,3')spiro((hexahydropyrrolo(1,2-a)pyrazine-1,4-dione)-6,3'-(2',3'-dihydrothieno(2,3-b)naphtho-4',9'-dione)); D000970:Antineoplastic Agents; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011804:Quinolines; D011809:Quinones; D017382:Reactive Oxygen Species; D013141:Spiro Compounds; D014746:Vimentin