Enhancement of docetaxel-induced cytotoxicity and apoptosis by all-trans retinoic acid (ATRA) through downregulation of survivin (BIRC5), MCL-1 and LTbeta-R in hormone- and drug resistant prostate cancer cell line, DU-145.
BACKGROUND
The management of hormone-refractory prostate cancer (HRPC) still remains as an important challenge of daily oncology practice. Docetaxel has proved to be a first line treatment choice. All-trans retinoic acid (ATRA) could potently inhibit the growth of prostate cancer cells in vitro and its combination with various anticancer agents results in increased cytotoxicity. Based on these data, our aim was to examine the synergistic/additive cytotoxic and apoptotic effects of combination of docetaxel and ATRA, in hormone- and drug refractory human DU-145 prostate cancer cells. Furthermore, we have searched for the underlying mechanisms of apoptosis by demonstrating apoptosis-related genes.


METHODS
XTT cell proliferation assay was used for showing cytotoxicity. For verifying apoptosis, both DNA Fragmentation by ELISA assay and caspase 3/7 activity measurement were used. For detecting the mechanism of apoptosis induced by docetaxel-ATRA combination, OligoGeArray which consists of 112 apoptosis related genes was used.


RESULTS
Our results revealed that docetaxel and ATRA were synergistically cytotoxic and apoptotic in DU-145 cells, in a dose- and time dependent manner. It was also shown by our studies that apoptosis was induced in DU-145 prostate carcinoma cells with significant cytotoxicity, no matter which agent applied first. We have found out that docetaxel-ATRA combination significantly downregulates survivin (BIRC5), myeloid cell leukemia-1 (MCL-1) and lymphotoxin beta-receptor (LTbetaR) genes, which all three have pivotal roles in regulation of apoptosis and cell cycle progression.


CONCLUSIONS
In conclusion, we strongly suggest that docetaxel and ATRA combination is a good candidate for this challenging era of daily oncologic practice. Also, the combination of docetaxel and ATRA might allow a reduction in docetaxel doses and by this way may diminish docetaxel adverse effects while maintaining the therapeutic effect in patients with HRPC.
Kucukzeybek
Yuksel
Y
Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine, Ege University, Bornova, Izmir, Turkey. yuksel.kucukzeybek@ege.edu.tr
Gul
Mustafa K
MK
Cengiz
Ercument
E
Erten
Cigdem
C
Karaca
Burcak
B
Gorumlu
Gurbuz
G
Atmaca
Harika
H
Uzunoglu
Selim
S
Karabulut
Bulent
B
Sanli
Ulus A
UA
Uslu
Ruchan
R
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use / Q000633:toxicity*; D017209:Apoptosis; D045744:Cell Line, Tumor; D000077143:Docetaxel; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D053259:Lymphotoxin beta Receptor / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D000077022:Survivin; D043823:Taxoids / Q000627:therapeutic use / Q000633:toxicity*; D014212:Tretinoin / Q000627:therapeutic use / Q000633:toxicity*
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D053259:Lymphotoxin beta Receptor; D008869:Microtubule-Associated Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D043823:Taxoids; D000077143:Docetaxel; D014212:Tretinoin
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