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Zoledronic acid induces antiproliferative and apoptotic effects in human pancreatic cancer cells in vitro.

Tassone P, Tagliaferri P, Viscomi C, Palmieri C, Caraglia M, D'Alessandro A, Galea E, Goel A, Abbruzzese A, Boland CR, Venuta S - Br. J. Cancer (2003)

Bottom Line: The proapoptotic effect was correlated to cleavage/activation of caspase-9 and poly(ADP)-ribose polymerase, but not of caspase-3.Finally, we observed that ZOL induces significant cytoskeletal rearrangements.In conclusion, we demonstrated that ZOL induces growth inhibition and apoptosis on PC cells and interferes with growth and survival pathways downstream to p21(ras).

View Article: PubMed Central - PubMed

Affiliation: Oncology Unit, Department of Experimental and Clinical Medicine, Via T. Campanella, 115 'Magna Graecia' University, 88100 Catanzaro, Italy. oncologia@unicz.it

ABSTRACT
Bisphosphonates (BPs) are an emerging class of drugs mostly used in the palliative care of cancer patients. We investigated the in vitro activity of the most potent antiresorptive BP, zoledronic acid (ZOL), on the growth and survival of three human pancreatic cancer (PC) cell lines (BxPC-3, CFPAC-1 and PANC-1). Pancreatic cancer frequently has a dysregulated p21(ras) pathway and therefore appears to be a suitable target for BPs that interfere with the prenylation of small GTP-binding proteins such as p21(ras). We found that ZOL induces growth inhibition (IC(50):10-50 micro M) and apoptotic death of PC cells. The proapoptotic effect was correlated to cleavage/activation of caspase-9 and poly(ADP)-ribose polymerase, but not of caspase-3. Moreover, we studied the p21(ras) signalling in cells exposed to ZOL and detected a reduction of p21(ras) and Raf-1 content and functional downregulation of the terminal enzyme ERK/MAPkinase and of the pKB/Akt survival pathway. Finally, we observed that ZOL induces significant cytoskeletal rearrangements. In conclusion, we demonstrated that ZOL induces growth inhibition and apoptosis on PC cells and interferes with growth and survival pathways downstream to p21(ras). These findings might be relevant for expanding application of BPs in cancer treatment.

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(A) Apoptotic effects induced by ZOL on CFPAC-1, PANC-1, BxPC-3 PC cancer cells. The analysis of apoptosis was performed after exposure to 50 μM of ZOL by flow cytometric detection of Annexin-V immunostaining. Cells were pulse exposed for 30, 60 and 180 min or continuously exposed to the drug. The PI method was used when apoptosis was evaluated 24 h after beginning treatment. Data are expressed as the mean value of at least four replicate experiments ±s.e. (B) Flow cytometric profiles from a representative experiment performed on CFPAC-1 cells. The percentage of apoptotic stained cells (%) is indicated in each quadrant.
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fig2: (A) Apoptotic effects induced by ZOL on CFPAC-1, PANC-1, BxPC-3 PC cancer cells. The analysis of apoptosis was performed after exposure to 50 μM of ZOL by flow cytometric detection of Annexin-V immunostaining. Cells were pulse exposed for 30, 60 and 180 min or continuously exposed to the drug. The PI method was used when apoptosis was evaluated 24 h after beginning treatment. Data are expressed as the mean value of at least four replicate experiments ±s.e. (B) Flow cytometric profiles from a representative experiment performed on CFPAC-1 cells. The percentage of apoptotic stained cells (%) is indicated in each quadrant.

Mentions: To clarify the mechanisms of ZOL-induced growth inhibition, we performed apoptotic assays on PC cells exposed to this compound. Activation of apoptosis was detected by Annexin-V staining, which is early expressed on the outer side of the cell membrane only when apoptosis is triggered and by PI which directly measures fragmented DNA. Figure 2Figure 2


Zoledronic acid induces antiproliferative and apoptotic effects in human pancreatic cancer cells in vitro.

Tassone P, Tagliaferri P, Viscomi C, Palmieri C, Caraglia M, D'Alessandro A, Galea E, Goel A, Abbruzzese A, Boland CR, Venuta S - Br. J. Cancer (2003)

(A) Apoptotic effects induced by ZOL on CFPAC-1, PANC-1, BxPC-3 PC cancer cells. The analysis of apoptosis was performed after exposure to 50 μM of ZOL by flow cytometric detection of Annexin-V immunostaining. Cells were pulse exposed for 30, 60 and 180 min or continuously exposed to the drug. The PI method was used when apoptosis was evaluated 24 h after beginning treatment. Data are expressed as the mean value of at least four replicate experiments ±s.e. (B) Flow cytometric profiles from a representative experiment performed on CFPAC-1 cells. The percentage of apoptotic stained cells (%) is indicated in each quadrant.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2741108&req=5

fig2: (A) Apoptotic effects induced by ZOL on CFPAC-1, PANC-1, BxPC-3 PC cancer cells. The analysis of apoptosis was performed after exposure to 50 μM of ZOL by flow cytometric detection of Annexin-V immunostaining. Cells were pulse exposed for 30, 60 and 180 min or continuously exposed to the drug. The PI method was used when apoptosis was evaluated 24 h after beginning treatment. Data are expressed as the mean value of at least four replicate experiments ±s.e. (B) Flow cytometric profiles from a representative experiment performed on CFPAC-1 cells. The percentage of apoptotic stained cells (%) is indicated in each quadrant.
Mentions: To clarify the mechanisms of ZOL-induced growth inhibition, we performed apoptotic assays on PC cells exposed to this compound. Activation of apoptosis was detected by Annexin-V staining, which is early expressed on the outer side of the cell membrane only when apoptosis is triggered and by PI which directly measures fragmented DNA. Figure 2Figure 2

Bottom Line: The proapoptotic effect was correlated to cleavage/activation of caspase-9 and poly(ADP)-ribose polymerase, but not of caspase-3.Finally, we observed that ZOL induces significant cytoskeletal rearrangements.In conclusion, we demonstrated that ZOL induces growth inhibition and apoptosis on PC cells and interferes with growth and survival pathways downstream to p21(ras).

View Article: PubMed Central - PubMed

Affiliation: Oncology Unit, Department of Experimental and Clinical Medicine, Via T. Campanella, 115 'Magna Graecia' University, 88100 Catanzaro, Italy. oncologia@unicz.it

ABSTRACT
Bisphosphonates (BPs) are an emerging class of drugs mostly used in the palliative care of cancer patients. We investigated the in vitro activity of the most potent antiresorptive BP, zoledronic acid (ZOL), on the growth and survival of three human pancreatic cancer (PC) cell lines (BxPC-3, CFPAC-1 and PANC-1). Pancreatic cancer frequently has a dysregulated p21(ras) pathway and therefore appears to be a suitable target for BPs that interfere with the prenylation of small GTP-binding proteins such as p21(ras). We found that ZOL induces growth inhibition (IC(50):10-50 micro M) and apoptotic death of PC cells. The proapoptotic effect was correlated to cleavage/activation of caspase-9 and poly(ADP)-ribose polymerase, but not of caspase-3. Moreover, we studied the p21(ras) signalling in cells exposed to ZOL and detected a reduction of p21(ras) and Raf-1 content and functional downregulation of the terminal enzyme ERK/MAPkinase and of the pKB/Akt survival pathway. Finally, we observed that ZOL induces significant cytoskeletal rearrangements. In conclusion, we demonstrated that ZOL induces growth inhibition and apoptosis on PC cells and interferes with growth and survival pathways downstream to p21(ras). These findings might be relevant for expanding application of BPs in cancer treatment.

Show MeSH
Related in: MedlinePlus