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A liposomal formulation of the synthetic curcumin analog EF24 (Lipo-EF24) inhibits pancreatic cancer progression: towards future combination therapies.

Bisht S, Schlesinger M, Rupp A, Schubert R, Nolting J, Wenzel J, Holdenrieder S, Brossart P, Bendas G, Feldmann G - J Nanobiotechnology (2016)

Bottom Line: Lipo-EF24 potently suppressed NF-kappaB nuclear translocation by inhibiting phosphorylation and subsequent degradation of its inhibitor I-kappa-B-alpha.In vivo, synergistic tumor growth inhibition was observed in MIAPaCa xenografts when Lipo-EF24 was given in combination with the standard-of-care cytotoxic agent gemcitabine.In line with in vitro observations, western blot analysis revealed decreased phosphorylation of I-kappa-B-alpha in excised Lipo-EF24-treated xenograft tumor tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine 3, Center of Integrated Oncology (CIO) Cologne-Bonn, University Hospital of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.

ABSTRACT

Background: Pancreatic cancer is one of the most lethal of human malignancies known to date and shows relative insensitivity towards most of the clinically available therapy regimens. 3,5-bis(2-fluorobenzylidene)-4-piperidone (EF24), a novel synthetic curcumin analog, has shown promising in vitro therapeutic efficacy in various human cancer cells, but insufficient water solubility and systemic bioavailability limit its clinical application. Here, we describe nano-encapsulation of EF24 into pegylated liposomes (Lipo-EF24) and evaluation of these particles in preclinical in vitro and in vivo model systems of pancreatic cancer.

Results: Transmission electron microscopy and size distribution studies by dynamic light scattering confirmed intact spherical morphology of the formed liposomes with an average diameter of less than 150 nm. In vitro, treatment with Lipo-EF24 induced growth inhibition and apoptosis in MIAPaCa and Pa03C pancreatic cancer cells as assessed by using cell viability and proliferation assays, replating and soft agar clonogenicity assays as well as western blot analyses. Lipo-EF24 potently suppressed NF-kappaB nuclear translocation by inhibiting phosphorylation and subsequent degradation of its inhibitor I-kappa-B-alpha. In vivo, synergistic tumor growth inhibition was observed in MIAPaCa xenografts when Lipo-EF24 was given in combination with the standard-of-care cytotoxic agent gemcitabine. In line with in vitro observations, western blot analysis revealed decreased phosphorylation of I-kappa-B-alpha in excised Lipo-EF24-treated xenograft tumor tissues.

Conclusion: Due to its promising therapeutic efficacy and favorable toxicity profile Lipo-EF24 might be a promising starting point for development of future combinatorial therapeutic regimens against pancreatic cancer.

No MeSH data available.


Related in: MedlinePlus

Growth inhibition of pancreatic cancer cell lines by EF24 and by curcumin. A panel of ten pancreatic cancer cell lines was exposed to increasing doses of a curcumin or b EF24 for 72 h, and cell viability was determined using MTS assays. Across all cell lines, EF24 inhibited viability at approximately 10- to 20-fold lower IC50 as compared to curcumin. c Similar effects were observed in clonogenic assays, where EF24 abrogated the ability of pancreatic cancer cells to form colonies at concentrations that were about tenfold lower than the required curcumin doses (all experiments were done in triplicates and repeated at least once; the figure shows pictures from two representative experiments)
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Fig1: Growth inhibition of pancreatic cancer cell lines by EF24 and by curcumin. A panel of ten pancreatic cancer cell lines was exposed to increasing doses of a curcumin or b EF24 for 72 h, and cell viability was determined using MTS assays. Across all cell lines, EF24 inhibited viability at approximately 10- to 20-fold lower IC50 as compared to curcumin. c Similar effects were observed in clonogenic assays, where EF24 abrogated the ability of pancreatic cancer cells to form colonies at concentrations that were about tenfold lower than the required curcumin doses (all experiments were done in triplicates and repeated at least once; the figure shows pictures from two representative experiments)

Mentions: The therapeutic activity of EF24 was tested and compared to its parent compound curcumin in a panel of ten different pancreatic cancer cell lines using MTS assays (Fig. 1a, b). As shown in the figure, EF24 inhibited net cell growth of pancreatic cancer cells in a dose dependent manner and with almost 10- to 20-fold lower IC50 as compared to curcumin across various cell lines. Moreover, EF24 also abrogated the ability of pancreatic cancer cells to form colonies at about 10-fold lower concentrations than curcumin in two different cell lines, MiaPaCa and Pa03C, respectively (Fig. 1c). Thus, our results show enhanced antineoplastic activity of EF24 on pancreatic cancer cell lines as compared to curcumin, which is in line with previous studies in other cancers [22–24].Fig. 1


A liposomal formulation of the synthetic curcumin analog EF24 (Lipo-EF24) inhibits pancreatic cancer progression: towards future combination therapies.

Bisht S, Schlesinger M, Rupp A, Schubert R, Nolting J, Wenzel J, Holdenrieder S, Brossart P, Bendas G, Feldmann G - J Nanobiotechnology (2016)

Growth inhibition of pancreatic cancer cell lines by EF24 and by curcumin. A panel of ten pancreatic cancer cell lines was exposed to increasing doses of a curcumin or b EF24 for 72 h, and cell viability was determined using MTS assays. Across all cell lines, EF24 inhibited viability at approximately 10- to 20-fold lower IC50 as compared to curcumin. c Similar effects were observed in clonogenic assays, where EF24 abrogated the ability of pancreatic cancer cells to form colonies at concentrations that were about tenfold lower than the required curcumin doses (all experiments were done in triplicates and repeated at least once; the figure shows pictures from two representative experiments)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4940769&req=5

Fig1: Growth inhibition of pancreatic cancer cell lines by EF24 and by curcumin. A panel of ten pancreatic cancer cell lines was exposed to increasing doses of a curcumin or b EF24 for 72 h, and cell viability was determined using MTS assays. Across all cell lines, EF24 inhibited viability at approximately 10- to 20-fold lower IC50 as compared to curcumin. c Similar effects were observed in clonogenic assays, where EF24 abrogated the ability of pancreatic cancer cells to form colonies at concentrations that were about tenfold lower than the required curcumin doses (all experiments were done in triplicates and repeated at least once; the figure shows pictures from two representative experiments)
Mentions: The therapeutic activity of EF24 was tested and compared to its parent compound curcumin in a panel of ten different pancreatic cancer cell lines using MTS assays (Fig. 1a, b). As shown in the figure, EF24 inhibited net cell growth of pancreatic cancer cells in a dose dependent manner and with almost 10- to 20-fold lower IC50 as compared to curcumin across various cell lines. Moreover, EF24 also abrogated the ability of pancreatic cancer cells to form colonies at about 10-fold lower concentrations than curcumin in two different cell lines, MiaPaCa and Pa03C, respectively (Fig. 1c). Thus, our results show enhanced antineoplastic activity of EF24 on pancreatic cancer cell lines as compared to curcumin, which is in line with previous studies in other cancers [22–24].Fig. 1

Bottom Line: Lipo-EF24 potently suppressed NF-kappaB nuclear translocation by inhibiting phosphorylation and subsequent degradation of its inhibitor I-kappa-B-alpha.In vivo, synergistic tumor growth inhibition was observed in MIAPaCa xenografts when Lipo-EF24 was given in combination with the standard-of-care cytotoxic agent gemcitabine.In line with in vitro observations, western blot analysis revealed decreased phosphorylation of I-kappa-B-alpha in excised Lipo-EF24-treated xenograft tumor tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine 3, Center of Integrated Oncology (CIO) Cologne-Bonn, University Hospital of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.

ABSTRACT

Background: Pancreatic cancer is one of the most lethal of human malignancies known to date and shows relative insensitivity towards most of the clinically available therapy regimens. 3,5-bis(2-fluorobenzylidene)-4-piperidone (EF24), a novel synthetic curcumin analog, has shown promising in vitro therapeutic efficacy in various human cancer cells, but insufficient water solubility and systemic bioavailability limit its clinical application. Here, we describe nano-encapsulation of EF24 into pegylated liposomes (Lipo-EF24) and evaluation of these particles in preclinical in vitro and in vivo model systems of pancreatic cancer.

Results: Transmission electron microscopy and size distribution studies by dynamic light scattering confirmed intact spherical morphology of the formed liposomes with an average diameter of less than 150 nm. In vitro, treatment with Lipo-EF24 induced growth inhibition and apoptosis in MIAPaCa and Pa03C pancreatic cancer cells as assessed by using cell viability and proliferation assays, replating and soft agar clonogenicity assays as well as western blot analyses. Lipo-EF24 potently suppressed NF-kappaB nuclear translocation by inhibiting phosphorylation and subsequent degradation of its inhibitor I-kappa-B-alpha. In vivo, synergistic tumor growth inhibition was observed in MIAPaCa xenografts when Lipo-EF24 was given in combination with the standard-of-care cytotoxic agent gemcitabine. In line with in vitro observations, western blot analysis revealed decreased phosphorylation of I-kappa-B-alpha in excised Lipo-EF24-treated xenograft tumor tissues.

Conclusion: Due to its promising therapeutic efficacy and favorable toxicity profile Lipo-EF24 might be a promising starting point for development of future combinatorial therapeutic regimens against pancreatic cancer.

No MeSH data available.


Related in: MedlinePlus