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FOXM1: A novel drug target in gastroenteropancreatic neuroendocrine tumors.

Briest F, Berg E, Grass I, Freitag H, Kaemmerer D, Lewens F, Christen F, Arsenic R, Altendorf-Hofmann A, Kunze A, Sänger J, Knösel T, Siegmund B, Hummel M, Grabowski P - Oncotarget (2015)

Bottom Line: In vitro inhibition by the FOXM1 inhibitor siomycin A led to down-regulation of mitotic proteins and resulted in a strong inhibitory effect.Siomycin A decreased mitosis rate, induced apoptosis in GEP-NEN cell lines and exerts synergistic effects with chemotherapy.FOXM1 is associated with clinical outcome and FOXM1 inhibition impairs survival in vitro.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Infectious Diseases, Rheumatology CC13, Medizinische Klinik 1, CBF, Germany.

ABSTRACT
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogeneous tumors that need to be molecularly defined to obtain novel therapeutic options. Forkheadbox protein M1 (FOXM1) is a crucial transcription factor in neoplastic cells and has been associated with differentiation and proliferation. We found that FOXM1 is strongly associated with tumor differentiation and occurrence of metastases in gastrointestinal NENs. In vitro inhibition by the FOXM1 inhibitor siomycin A led to down-regulation of mitotic proteins and resulted in a strong inhibitory effect. Siomycin A decreased mitosis rate, induced apoptosis in GEP-NEN cell lines and exerts synergistic effects with chemotherapy. FOXM1 is associated with clinical outcome and FOXM1 inhibition impairs survival in vitro. We therefore propose FOXM1 as novel therapeutic target in GEP-NENs.

No MeSH data available.


Related in: MedlinePlus

Cytotoxic effects of siomycin A treatment in vitroBON A., LCC-18 B., QGP-1 C., and KRJ-1 D. cells were treated with 1 and 2μM siomycin A versus 0.04% DMSO, 0.01μM Everolimus and 1% Triton X (total cell lysis control) for 4 and 24 hours. LDH release from necrotic cells was colorimetrically measured in % of Triton X lysed cell control by LDH cytotoxicity assay. Dotted line indicates 20%. BON and LCC-18 cells showed very low spontaneous cytotoxicity (lower than 20%). QGP-1 cells had cytotoxic effects in the range of 20%. Only KRJ-1 cells had higher cytotoxicity values up to 63%. Further studies should be performed to assess the in vivo tolerability of siomycin A.
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Figure 6: Cytotoxic effects of siomycin A treatment in vitroBON A., LCC-18 B., QGP-1 C., and KRJ-1 D. cells were treated with 1 and 2μM siomycin A versus 0.04% DMSO, 0.01μM Everolimus and 1% Triton X (total cell lysis control) for 4 and 24 hours. LDH release from necrotic cells was colorimetrically measured in % of Triton X lysed cell control by LDH cytotoxicity assay. Dotted line indicates 20%. BON and LCC-18 cells showed very low spontaneous cytotoxicity (lower than 20%). QGP-1 cells had cytotoxic effects in the range of 20%. Only KRJ-1 cells had higher cytotoxicity values up to 63%. Further studies should be performed to assess the in vivo tolerability of siomycin A.

Mentions: To distinguish whether cells undergo apoptosis or necrosis, we completed our analyses by an LDH-based cytotoxicity assay. Siomycin A in effective doses showed a low cytotoxic effect on BON, QGP-1 and LCC-18 (Figure 6 A-C). Only in KRJ-1 there were strong cytotoxic effects, presumably due to the loss of intercellular contact. As resuspending the cell clusters was obligatory for equal cell numbers and the time of incubation was too short for a reattachment, induction of anoikis might be an explanation for an early and strong loss of membrane integrity (Figure 6D).


FOXM1: A novel drug target in gastroenteropancreatic neuroendocrine tumors.

Briest F, Berg E, Grass I, Freitag H, Kaemmerer D, Lewens F, Christen F, Arsenic R, Altendorf-Hofmann A, Kunze A, Sänger J, Knösel T, Siegmund B, Hummel M, Grabowski P - Oncotarget (2015)

Cytotoxic effects of siomycin A treatment in vitroBON A., LCC-18 B., QGP-1 C., and KRJ-1 D. cells were treated with 1 and 2μM siomycin A versus 0.04% DMSO, 0.01μM Everolimus and 1% Triton X (total cell lysis control) for 4 and 24 hours. LDH release from necrotic cells was colorimetrically measured in % of Triton X lysed cell control by LDH cytotoxicity assay. Dotted line indicates 20%. BON and LCC-18 cells showed very low spontaneous cytotoxicity (lower than 20%). QGP-1 cells had cytotoxic effects in the range of 20%. Only KRJ-1 cells had higher cytotoxicity values up to 63%. Further studies should be performed to assess the in vivo tolerability of siomycin A.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480744&req=5

Figure 6: Cytotoxic effects of siomycin A treatment in vitroBON A., LCC-18 B., QGP-1 C., and KRJ-1 D. cells were treated with 1 and 2μM siomycin A versus 0.04% DMSO, 0.01μM Everolimus and 1% Triton X (total cell lysis control) for 4 and 24 hours. LDH release from necrotic cells was colorimetrically measured in % of Triton X lysed cell control by LDH cytotoxicity assay. Dotted line indicates 20%. BON and LCC-18 cells showed very low spontaneous cytotoxicity (lower than 20%). QGP-1 cells had cytotoxic effects in the range of 20%. Only KRJ-1 cells had higher cytotoxicity values up to 63%. Further studies should be performed to assess the in vivo tolerability of siomycin A.
Mentions: To distinguish whether cells undergo apoptosis or necrosis, we completed our analyses by an LDH-based cytotoxicity assay. Siomycin A in effective doses showed a low cytotoxic effect on BON, QGP-1 and LCC-18 (Figure 6 A-C). Only in KRJ-1 there were strong cytotoxic effects, presumably due to the loss of intercellular contact. As resuspending the cell clusters was obligatory for equal cell numbers and the time of incubation was too short for a reattachment, induction of anoikis might be an explanation for an early and strong loss of membrane integrity (Figure 6D).

Bottom Line: In vitro inhibition by the FOXM1 inhibitor siomycin A led to down-regulation of mitotic proteins and resulted in a strong inhibitory effect.Siomycin A decreased mitosis rate, induced apoptosis in GEP-NEN cell lines and exerts synergistic effects with chemotherapy.FOXM1 is associated with clinical outcome and FOXM1 inhibition impairs survival in vitro.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Infectious Diseases, Rheumatology CC13, Medizinische Klinik 1, CBF, Germany.

ABSTRACT
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogeneous tumors that need to be molecularly defined to obtain novel therapeutic options. Forkheadbox protein M1 (FOXM1) is a crucial transcription factor in neoplastic cells and has been associated with differentiation and proliferation. We found that FOXM1 is strongly associated with tumor differentiation and occurrence of metastases in gastrointestinal NENs. In vitro inhibition by the FOXM1 inhibitor siomycin A led to down-regulation of mitotic proteins and resulted in a strong inhibitory effect. Siomycin A decreased mitosis rate, induced apoptosis in GEP-NEN cell lines and exerts synergistic effects with chemotherapy. FOXM1 is associated with clinical outcome and FOXM1 inhibition impairs survival in vitro. We therefore propose FOXM1 as novel therapeutic target in GEP-NENs.

No MeSH data available.


Related in: MedlinePlus