In vitro cytotoxic effects of imatinib in combination with anticancer drugs in human prostate cancer cell lines

Kübler, Hubert; Randenborgh, H. Van; Treiber, Uwe; Wutzler, Sebastian; Battistel, Carolus; Lehmer, A.; Wagenpfeil, Stefan; Härtung, R.; Paul, R.

doi:10.1002/pros.20201

Cited by 37 publications

(29 citation statements)

References 27 publications

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“…When we compared the cytotoxic activity of Teucrium persicum with that of some known anti-cancer drugs, we found that the IC 50 value of Teucrium persicum extract for PC-3 cells was much lower. The IC 50 values reported for doxorubicin, imatinib and etoposide against PC-3 cells are 500, 5700 and 1730 μg/ml respectively (Kubler et al, 2005;Dudley et al, 2008;Tsakalozou et al, 2012) which are much higher than that of Teucrium persicum extract (142μg/ml).…”

Section: Discussionmentioning

confidence: 76%

Anticancer Properties of Teucrium persicum in PC-3 Prostate Cancer Cells

Tafrihi

Toosi²,

Minaei³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Crude extracts or phytochemicals obtained from some plants have potential anti-cancer properties. Teucrium persicum is an Iranian endemic plant belonging to the Lamiaceae family which has traditionally been used to relieve abdominal pains. However, the anti-cancer properties of this species of the Teucrium genus have not been investigated previously. In this study, we have used a highly invasive prostate cancer cell line, PC-3, which is an appropriate cell system to study anti-tumor properties of plants. A methanolic extract obtained from T persicum potently inhibited viability of PC-3 cells. The viability of SW480 colon and T47D breast cancer cells was also significantly decreased in the presence of the T persicum extract. Flow cytometry suggested that the reduction of cell viability was due to induction of apoptosis. In addition, the results of wound healing and gelatin zymography experiments supported anti-cell invasion activity of T persicum. Interestingly, sublethal concentrations of T persicum extract induced an epithelial-like morphology in a subpopulation of cells with an increase in E-Cadherin and β-Catenin protein levels at the cell membrane. These results strongly suggest that T persicum is a plant with very potent anti-tumor activity

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Section: Discussionmentioning

confidence: 76%

Anticancer Properties of Teucrium persicum in PC-3 Prostate Cancer Cells

Tafrihi

Toosi²,

Minaei³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…Our data suggest a strong association between imatinib therapy and systemic p-PDGFR inhibition consistent with the known effect of the drug but we found that for the study population as a whole, increasing p-PDGFR inhibition was associated with a diminished probability of a PSA decline by 50% and a trend toward shorter PFS. These findings are of concern in light of a report that imatinib had antagonistic effects against docetaxel in PC3 cells (30). Although we have been unable to duplicate such in vitro findings, the implications of our experimental results may require further scrutiny in studies involving PDGFR inhibitors combined with taxanes in other neoplasms (7,8).…”

Section: Discussionmentioning

confidence: 80%

Platelet-Derived Growth Factor Receptor Inhibition and Chemotherapy for Castration-Resistant Prostate Cancer with Bone Metastases

Mathew

Thall

Bucana³

et al. 2007

Clinical Cancer Research

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Purpose:To further assess preclinical and early clinical evidence that imatinib mesylate, a plateletderived growth factor receptor (PDGFR) inhibitor, modulates taxane activity in prostate cancer and bone metastases, a randomized study was conducted. Experimental Design: Men with progressive castration-resistant prostate cancer with bone metastases (n = 144) were planned for equal randomization to i.v. 30 mg/m 2 docetaxel on days 1, 8, 15, and 22 every 42 days with 600 mg imatinib daily or placebo, for an improvement in median progression-free survival from 4.5 to 7.5 months (two-sided a = 0.05 and b = 0.20). Secondary end points included differential toxicity and bone turnover markers, tumor phosphorylated PDGFR (p-PDGFR) expression, and modulation of p-PDGFR in peripheral blood leukocytes. Results: Accrual was halted early because of adverse gastrointestinal events. Among 116 evaluable men (57 docetaxel + imatinib; 59 docetaxel + placebo), respective median times to progression were 4.2 months (95% confidence interval, 3.1-7.5) and 4.2 months (95% confidence interval, 3.0-6.8; P = 0.58, log-rank test). Excess grade 3 toxicities (n = 23) in the docetaxel + imatinib group were principally fatigue and gastrointestinal. Tumor p-PDGFR expression was observed in 12 of 14 (86%) evaluable bone specimens. In peripheral blood leukocytes, p-PDGFR reduction was more likely in docetaxel + imatinib^treated patients compared with docetaxel + placebo (P < 0.0001), as were reductions in urine N-telopeptides (P = 0.004) but not serum bone-specific alkaline phosphatase (P = 0.099). Conclusions: These clinical and translational results question the value of PDGFR inhibition with taxane chemotherapy in prostate cancer bone metastases and are at variance with the preclinical studies. This discordance requires explanation.The metastatic phenotype of prostate cancer is highly conserved and characterized by osteoblastic bone metastases, the burden of which correlates with morbidity and mortality from the disease (1). Clarification of the molecular basis of disease progression in bone is expected to yield therapeutic strategies that may significantly transform the natural history of the disease.Several lines of evidence have implicated the platelet-derived growth factor receptor (PDGFR) in the progression of prostate cancer bone metastases. Amplification of conserved domains of tyrosine kinase receptors using degenerate primers identified PDGFR as the most commonly amplified transcript from pooled aspirate specimens from prostate cancer bone metastases (2). Immunohistochemical staining has shown high frequencies of PDGFR expression in prostate cancer bone metastases (2, 3). Our preclinical findings from an orthotopic model of prostate cancer bone metastases showed that PDGFR expression was up-regulated in PC3-MM2 cells and associated vascular endothelium within the bone microenvironment, suggestive of an organ-specific paracrine effect (4). Further, combining the PDGFR inhibitor imatinib mesylate (5) with

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“…In vitro studies showed that the IC 50 of imatinib on PDGFR highly expressed tumor cell lines, such as prostate, ovarian, and cervical cancer, was in the 10-15 µM range, which is far higher than the plasma concentration arising from the usual imatinib dose of 400 mg/day. 9,[15][16][17] Furthermore, nonspecific drug binding in the plasma, particularly alpha-1-acid glycoprotein (AGP) binding can decrease the free, and therefore active, concentration of the drug, and hence reduce the tumor cellular concentration of imatinib. 18 Therefore, considering the referred nonspecific drug binding with AGP and the fact that the allowed imatinib dose cannot reach the effective cancer cellular concentration, we hypothesized that loading of imatinib in a drug delivery system would be a promising therapeutic approach in cervical cancer.…”

Section: Introductionmentioning

confidence: 99%

Folate receptor-targeted liposomes enhanced the antitumor potency of imatinib through the combination of active targeting and molecular targeting

Ye¹,

Zhang²,

Tan³

et al. 2014

IJN

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Purpose Imatinib inhibits platelet-derived growth factor receptor (PDGFR), and evidence shows that PDGFR participates in the development and progression of cervical cancer. Although imatinib has exhibited preclinical activity against cervical cancer, only minimal clinical therapeutic efficacy was observed. This poor therapeutic efficacy may be due to insufficient drug delivery to the tumor cells and plasma protein binding. Therefore, the purpose of this study was to explore a novel folate receptor (FR)-targeted delivery system via imatinib-loaded liposomes to enhance drug delivery to tumor cells and to reduce plasma protein binding. Methods Imatinib was remote-loaded into FR-targeted liposomes which were prepared by thin film hydration followed by polycarbonate membrane extrusion. Encapsulation efficiency, mean size diameter, and drug retention were characterized and cellular uptake, cell cytotoxicity, and cell apoptosis on cervical cancer HeLa cells were evaluated. Comparative pharmacokinetic studies were also carried out with FR-targeted imatinib liposomes, simple imatinib liposomes, and free imatinib. Results High encapsulation efficiency (>90%), appropriate mean particle size (143.5 nm), and zeta potential (−15.97 mV) were obtained for FR-targeted imatinib liposomes. The drug release profile showed minimal imatinib leakage (<5%) in phosphate-buffered saline (PBS) at pH =7.4 within 72 hours of incubation, while more leakage (>25%) was observed in PBS at pH =5.5. This indicates that these liposomes possess a certain degree of pH sensitivity. Cytotoxicity assays demonstrated that the FR-targeted imatinib liposomes promoted a six-fold IC 50 reduction on the non-targeted imatinib liposomes from 910 to 150 μM. In addition, FR-targeted imatinib liposomes enhanced HeLa cell apoptosis in vitro compared to the non-targeted imatinib liposomes. Pharmacokinetic parameters indicated that both targeted and non-targeted liposomes exhibited long circulation properties in Kunming mice. Conclusion These findings indicate that the nano-sized FR-targeted PDGFR antagonist imatinib liposomes may constitute a promising strategy in cervical cancer therapy through the combination of active targeting and molecular targeting.

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In vitro cytotoxic effects of imatinib in combination with anticancer drugs in human prostate cancer cell lines

Cited by 37 publications

References 27 publications

Anticancer Properties of Teucrium persicum in PC-3 Prostate Cancer Cells

Anticancer Properties of Teucrium persicum in PC-3 Prostate Cancer Cells

Platelet-Derived Growth Factor Receptor Inhibition and Chemotherapy for Castration-Resistant Prostate Cancer with Bone Metastases

Folate receptor-targeted liposomes enhanced the antitumor potency of imatinib through the combination of active targeting and molecular targeting

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