Topotecan as a molecular targeting agent which blocks the Akt and VEGF cascade in platinum-resistant ovarian cancers

Tsunetoh, Satoshi; Sasaki, Hiroshi; Tanabe, Akiko; Tanaka, Yoshimichi; Sekijima, Tatsuharu; Fujioka, Satoe; Kawaguchi, Hiroshi; Kanemura, Masanori; Yamashita, Yoshiki; Ohmichi, Masahide

doi:10.4161/cbt.10.11.13443

Cited by 24 publications

(21 citation statements)

References 31 publications

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“…NO interferes with caspase activity by S-nitrosation of the active site (29), and also by impairing the cleavage of proenzymes, which is required for their activation (16,24). On the contrary, HIF-1α, whose degradation is governed by PHD2, favors several aspects of tumorigenesis, including resistance to chemotherapy and radiation therapy (38,39). NO promotes stabilization of HIF-1α directly, via S-nitrosation of its oxygen-dependent domain (33), or indirectly, by inhibiting PHD2 (30,34).…”

Section: Discussionmentioning

confidence: 99%

Endogenously produced nitric oxide mitigates sensitivity of melanoma cells to cisplatin

Godoy¹,

Anderson²,

Chowdhury³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Melanoma patients experience inferior survival after biochemotherapy when their tumors contain numerous cells expressing the inducible isoform of NO synthase (iNOS) and elevated levels of nitrotyrosine, a product derived from NO. Although several lines of evidence suggest that NO promotes tumor growth and increases resistance to chemotherapy, it is unclear how it shapes these outcomes. Here we demonstrate that modulation of NOmediated S-nitrosation of cellular proteins is strongly associated with the pattern of response to the anticancer agent cisplatin in human melanoma cells in vitro. Cells were shown to express iNOS constitutively, and to generate sustained nanomolar levels of NO intracellularly. Inhibition of NO synthesis or scavenging of NO enhanced cisplatin-induced apoptotic cell death. Additionally, pharmacologic agents disrupting S-nitrosation markedly increased cisplatin toxicity, whereas treatments favoring stabilization of S-nitrosothiols (SNOs) decreased its cytotoxic potency. Activity of the proapoptotic enzyme caspase-3 was higher in cells treated with a combination of cisplatin and chemicals that decreased NO/ SNOs, whereas lower activity resulted from cisplatin combined with stabilization of SNOs. Constitutive protein S-nitrosation in cells was detected by analysis with biotin switch and reduction/ chemiluminescence techniques. Moreover, intracellular NO concentration increased significantly in cells that survived cisplatin treatment, resulting in augmented S-nitrosation of caspase-3 and prolyl-hydroxylase-2, the enzyme responsible for targeting the prosurvival transcription factor hypoxia-inducible factor-1α for proteasomal degradation. Because activities of these enzymes are inhibited by S-nitrosation, our data thus indicate that modulation of intrinsic intracellular NO levels substantially affects cisplatin toxicity in melanoma cells. The underlying mechanisms may thus represent potential targets for adjuvant strategies to improve the efficacy of chemotherapy.chemoresistance | cancer | caspase-3

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Section: Discussionmentioning

confidence: 99%

Endogenously produced nitric oxide mitigates sensitivity of melanoma cells to cisplatin

Godoy¹,

Anderson²,

Chowdhury³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…7 Although it is not the case of OCCC, we have previously reported that the activation of the PI3K pathway via cisplatin, a platinum-based anti-cancer drug, in cisplatinresistant ovarian cancers resulted in overexpression and nuclear accumulation of HIF-1a. 10 Rapamycin analogs, mTOR inhibitors, such as orally administered everolimus and intravenously administered temsirolimus have been used in the treatment of advanced renal cell carcinomas and are currently considered as a potential therapeutic regimen for OCCC. The biggest problem of molecular target drugs is the occurrence of resistance.…”

Section: Introductionmentioning

confidence: 99%

Crosstalk between PI3K and Ras pathways via protein phosphatase 2A in human ovarian clear cell carcinoma

Takai¹,

Nakagawa

Tanabe

et al. 2015

Cancer Biology & Therapy

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Hypoxia-inducible factor-1 (HIF-1) is one of the most promising pharmacological targets for all types of cancer, including ovarian cancer. Ovarian clear cell carcinoma (OCCC) has poor prognosis because of its insensitivity to chemotherapy. To elucidate the characteristics of this troublesome cancer, we examined HIF-1α expression under normoxia or hypoxia in various ovarian cancer cell lines. HIF-1α was highly expressed under normoxia only in RMG-1, an OCCC cell line. To examine whether HIF-1 is involved in the tumorigenesis of RMG-1 cells, we established HIF-1α-silenced cells, RMG-1HKD. The proliferation rate of RMG-1HKD cells was faster than that of RMG-1 cells. Furthermore, the activity of MEK/ERK in the Ras pathway increased in RMG-1HKD cells, whereas that of mTOR in the PI3K pathway did not change. Activation of the Ras pathway was attributable to the increase in phosphorylated MEK via PP2A inactivation. To confirm the crosstalk between the PI3K and Ras pathways in vivo, RMG-1 or RMG-1HKD cells were transplanted into the skin of nude mice with rapamycin (an inhibitor of mTOR), PD98059 (an inhibitor of MEK), or both. RMG-1HKD cells showed higher sensitivity to PD98059 than that observed in RMD-1 cells, whereas the combination therapy resulted in synergistic inhibition of both cells. These findings suggest that inhibition of HIF-1, a downstream target of mTOR in the PI3K pathway, activates the Ras pathway on account of the increase in MEK phosphorylation via PP2A inactivation, and the crosstalk between the 2 pathways could be applied in the combination therapy for HIF-1-overexpressing cancers such as OCCC.

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“…20–24 Thereafter, as derivatives/analogues of CPT, topotecan and irinotecan ((CPT)-II) were successfully developed and are currently in clinical use for treatment of ovarian cancer and colon cancer, respectively. 25–26,27–28 CPT acts by stabilizing the cleavage complex and preventing the relegation step. The binding of CPT to the cleavage complex is considered to be reversible, but the compound becomes lethal due to the collision of the stalled enzyme-DNA complex with the replication fork.…”

Section: Introductionmentioning

confidence: 99%

Microscopic modes and free energies for topoisomerase I-DNA covalent complex binding with non-camptothecin inhibitors by molecular docking and dynamics simulations

et al. 2013

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Topoisomerase I (Topo1) has been identified as an attractive target for anticancer drug development due to its central role in facilitating the nuclear process of the DNA. It is essential for rational design of novel Topo1 inhibitors to reliably predict the binding structures of the Topo1 inhibitors interacting with the Topo1-DNA complex. The detailed binding structures and binding free energies for the Topo1-DNA complex interacting with typical non-camptothecin (CPT) Topo1 inhibitors have been examined by performing molecular docking, molecular dynamic (MD) simulations, and binding free energy calculations. The computational results provide valuable insights into the binding modes of the inhibitors binding with the Topo1-DNA complex and the key factors affecting the binding affinity. It has been demonstrated that the — stacking interaction with the DNA base pairs and the hydrogen bonding with Topo1 have the pivotal contributions to the binding structures and binding free energies, although the van der Waals and electrostatic interactions also significantly contribute to the stabilization of the binding structures. The calculated binding free energies are in good agreement with the available experiment activity data. The detailed binding modes and the crucial factors affecting the binding free energies obtained from the present computational studies may provide valuable insights for future rational design of novel, more potent Topo1 inhibitors.

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Topotecan as a molecular targeting agent which blocks the Akt and VEGF cascade in platinum-resistant ovarian cancers

Cited by 24 publications

References 31 publications

Endogenously produced nitric oxide mitigates sensitivity of melanoma cells to cisplatin

Endogenously produced nitric oxide mitigates sensitivity of melanoma cells to cisplatin

Crosstalk between PI3K and Ras pathways via protein phosphatase 2A in human ovarian clear cell carcinoma

Microscopic modes and free energies for topoisomerase I-DNA covalent complex binding with non-camptothecin inhibitors by molecular docking and dynamics simulations

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