Cytotoxicity of 2,3-dichloro-5,8-dimethoxy-1,4-naphthoquinone in androgen-dependent and -independent prostate cancer cell lines.
BACKGROUND
Prostate cancer ranks third worldwide in cancer incidence and sixth in cancer mortality among men. A number of 1,4-naphthoquinone derivatives have been found to possess significant pharmacological effects associated with marked antimicrobial and antitumor activities. In the present study the in vitro effect of 2,3-dichloro-5,8-dimethoxy-1,4-naphthoquinone (DCDMNQ) was evaluated on androgen-dependent (LNCaP, CWR-22) and androgen-independent (PC-3. DU-145) human prostate cancer cell lines, and/or a normal bone marrow cell line (HS-5). Moreover, the in vitro activity of this compound on cell cycle regulation and apoptosis was evaluated.


METHODS
Established methods of cell viability, cell cycle, Western blot and apoptosis were used.


RESULTS
The effect of DCDMNQ on LNCaP, CWR-22, PC-3, DU-145 and HS-5 cells revealed significant anti-tumor activities with IC50s, of 1, 3. 1.5, 3 and 10 microM respectively. Cell cycle analysis showed that DCDMNQ inhibited progression through the cell cycle in PC-3 and DU-145 cell lines in a time-dependent manner. The result for the CWR-22 cell line showed that DCDMNQ arrested cells in the G -phase of the cell cycle with the greatest proportion of cells in the G1-phase by day 5; however, the LNCaP cell line was inconsistent. The compound showed no effect on the cell cycle progression in the bone marrow HS-5 cell line. These findings were further validated using Western blot analysis. Furthermore, DCDMNQ induced apoptosis in the androgen-independent cells, preferentially over that of the androgen-dependent cell lines, in a time-dependent manner.


CONCLUSIONS
Although the mechanism of action of this compound has not been completely elucidated, the effect on the cell cycle and the induction of apoptosis in different prostate cancer cell lines prompted us to carry out a more in-depth preclinical evaluation of it. This study suggests that DCDMNQ may have an impact on treatment of prostate cancer while protecting the bone marrow.
Copeland
Robert L
RL
Department of Pharmacology, College of Medicine and Cancer Center, Howard University, Washington, DC 20059, USA. rlcopeland@howard.edu
Das
Jharna R
JR
Bakare
Oladapo
O
Enwerem
Nkechi M
NM
Berhe
Solomon
S
Hillaire
Kenguele
K
White
Douglas
D
Beyene
Desta
D
Kassim
Olakunle O
OO
Kanaan
Yasmine M
YM
D000728:Androgens / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D009285:Naphthoquinones / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000032:analysis / Q000378:metabolism
C521356:2,3-dichloro-5,8-dimethoxy-1,4-naphthoquinone; D000728:Androgens; D000970:Antineoplastic Agents; D009285:Naphthoquinones; D016160:Retinoblastoma Protein