TY - JOUR
T1 - Sequence-dependent antitumor effects of differentiation agents in combination with cell cycle-dependent cytotoxic drugs
AU - Verheul, Henk M.W.
AU - Qian, David Z.
AU - Carducci, Michael A.
AU - Pili, Roberto
N1 - Funding Information:
This study was supported in part by NIH Grants K08-CA69164, R01-CA75525, CaPCURE. Grant (M.A.C.) and DOD-DAMD17-02-1-0077 (R.P.).
PY - 2007/8
Y1 - 2007/8
N2 - Purpose: Combination of two differentiation agents such as phenylbutyrate (PB) and 13-cis-retinoic acid (CRA) has been shown to have an additive inhibitory effect on tumor growth in preclinical studies. In this report we explored the hypotheses that these "cytostatic" agents may have a greater antitumor activity in combination with "cytotoxic" compounds and their biological effect may be sequence-dependent. Methods: The antitumor activity of combination of PB and CRA with paclitaxel (TX ) and doxorubicin (DOXO) on human prostate and colon carcinoma cell lines was assessed both in vitro and in vivo. The effect on cell cycle, apoptotic rate, cycline expression and induction of p21 expression was also determined. Results: Following treatment of tumor cells with PB + CRA + TX or DOXO, inhibition of tumor cell growth was greatly enhanced as compared to PB + CRA, TX or DOXO alone, with >90% growth inhibition. However, when the cells were pretreated with PB + CRA followed by TX or DOXO, the enhanced inhibition was abolished suggesting a protective effect to this sequence. Interestingly treatment with PB + CRA restored sensitivity to DOXO in PC-3 human prostate cancer cell line. PB + CRA induced p21 expression and cell-cycle arrest in G1 phase, while TX and DOXO induced G2/M arrest. p21 and p53-deficient colon carcinoma cell lines were more sensitive to the effect of PB + CRA and TX as single agents and in combination, as compared to the wild type cells. When p21-deficient cells were pretreated with PB + CRA followed by TX the protective effect was still observed. Treatment of tumor cells with combination of these drugs induced cell cycle delay at multiple mitotic checkpoints before undergoing apoptosis. Tumor growth was significantly inhibited and delayed in animals treated with either TX or concomitantly with TX and PB + CRA as compared to control. Animals treated with all three agents demonstrated further growth inhibition or delay than the TX alone or PB + CRA arm. Conclusions: These results suggest a rational therapeutic approach for combination of differentiation-inducing agents with cytotoxic drugs given concomitantly, but not sequentially.
AB - Purpose: Combination of two differentiation agents such as phenylbutyrate (PB) and 13-cis-retinoic acid (CRA) has been shown to have an additive inhibitory effect on tumor growth in preclinical studies. In this report we explored the hypotheses that these "cytostatic" agents may have a greater antitumor activity in combination with "cytotoxic" compounds and their biological effect may be sequence-dependent. Methods: The antitumor activity of combination of PB and CRA with paclitaxel (TX ) and doxorubicin (DOXO) on human prostate and colon carcinoma cell lines was assessed both in vitro and in vivo. The effect on cell cycle, apoptotic rate, cycline expression and induction of p21 expression was also determined. Results: Following treatment of tumor cells with PB + CRA + TX or DOXO, inhibition of tumor cell growth was greatly enhanced as compared to PB + CRA, TX or DOXO alone, with >90% growth inhibition. However, when the cells were pretreated with PB + CRA followed by TX or DOXO, the enhanced inhibition was abolished suggesting a protective effect to this sequence. Interestingly treatment with PB + CRA restored sensitivity to DOXO in PC-3 human prostate cancer cell line. PB + CRA induced p21 expression and cell-cycle arrest in G1 phase, while TX and DOXO induced G2/M arrest. p21 and p53-deficient colon carcinoma cell lines were more sensitive to the effect of PB + CRA and TX as single agents and in combination, as compared to the wild type cells. When p21-deficient cells were pretreated with PB + CRA followed by TX the protective effect was still observed. Treatment of tumor cells with combination of these drugs induced cell cycle delay at multiple mitotic checkpoints before undergoing apoptosis. Tumor growth was significantly inhibited and delayed in animals treated with either TX or concomitantly with TX and PB + CRA as compared to control. Animals treated with all three agents demonstrated further growth inhibition or delay than the TX alone or PB + CRA arm. Conclusions: These results suggest a rational therapeutic approach for combination of differentiation-inducing agents with cytotoxic drugs given concomitantly, but not sequentially.
KW - Cell cycle
KW - Cytotoxic drugs
KW - Differentiation agents
KW - Prostate cancer
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U2 - 10.1007/s00280-006-0379-2
DO - 10.1007/s00280-006-0379-2
M3 - Article
C2 - 17256134
AN - SCOPUS:34250641175
SN - 0344-5704
VL - 60
SP - 329
EP - 339
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 3
ER -