The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells

Iuliis, Francesca De; Taglieri, Ludovica; Salerno, Gerardo; Giuffrida, A. M.; Milana, Bernardina; Giantulli, Sabrina; Carradori, Simone; Silvestri, Ida; Scarpa, Susanna

doi:10.1007/s10637-016-0345-8

Cited by 22 publications

(17 citation statements)

References 33 publications

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“…Consequently, two cell lines that responded differently to RAD001 were selected: One sensitive (BT474) and the other resistant (MCF7). Our group has previously demonstrated that the upregulation of survivin, a specific IAP component, contributes to establishing resistance to taxanes and kinesin inhibitors in breast cancer cells (11,12). Survivin is a downstream target of the PI3k/Akt/mTOR pathway that is involved in drug resistance (18).…”

Section: Discussionmentioning

confidence: 99%

“…Our group previously demonstrated that the upregulation of one of these IAPs, survivin, is involved in the resistance of human breast cancer cells to taxanes and also to K858, an inhibitor of kinesins (11,12). Given that survivin and estrogens are involved in the PI3k/Akt/mTOR transduction pathway, it is possible to hypothesize that survivin may be involved in the establishment of RAD001 resistance in certain hormone-responsive breast cancers.…”

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confidence: 99%

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Resistance to the mTOR inhibitor everolimus is reversed by the downregulation of survivin in breast cancer cells

et al. 2017

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Abstract. Everolimus (RAD001) is an inhibitor of mammalian target of rapamycin used in combination with exemestane to treat hormone receptor-positive advanced breast cancer. However, not all patients are equally sensitive to RAD001 and certain patients develop resistance. Therefore, the present study analyzed the mechanisms involved in the resistance of breast cancer cells to RAD001 in order to identify a potential tool to overcome it. The effects of RAD001 on the inhibition of cell viability, on the induction of apoptosis and autophagy and on the regulation of survivin, an anti-apoptotic protein, were evaluated in two breast cancer cell lines: BT474 (luminal B) and MCF7 (luminal A). RAD001 was demonstrated to induce autophagy in the two cell lines at following a short period of treatment (4 h) and to induce apoptosis exclusively in BT474 cells following longer periods of treatment (48 h). RAD001 induced the downregulation of survivin in BT474 cells and its upregulation in MCF7 cells. Consequently, inhibiting survivin with YM155 resulted in the acquired resistance of MCF7 cells to RAD001 being reverted, restoring RAD001-induced apoptosis. These data demonstrated that RAD001 exerted anti-proliferative and pro-apoptotic effects on breast cancer cells, but that these effects were repressed by the simultaneous up-regulation of survivin. Finally, the results demonstrated that inhibiting the expression of survivin resulted in the restoration of the anti-neoplastic activity of RAD001.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Resistance to the mTOR inhibitor everolimus is reversed by the downregulation of survivin in breast cancer cells

et al. 2017

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“…This impaired proliferation and induced apoptosis in MCF-7 and MDA231 cells, and it induced angiogenesis in vitro and in vivo [26]. Another KIF11 inhibitor, K85, was shown to have anticancer activity in breast cancer, though it also contributed to chemoresistance [27]. Adding to this existing research, we showed that there was a clinical association between the expression of KIF11 and breast cancer.…”

Section: Discussionmentioning

confidence: 84%

KIF11 Functions as an Oncogene and Is Associated with Poor Outcomes from Breast Cancer

et al. 2019

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Purpose The study aimed to search and identify genes that were differentially expressed in breast cancer, and their roles in cancer growth and progression. Materials and Methods The Gene Expression Omnibus (Oncomine) and The Cancer Genome Atlas databases ( https://cancergenome.nih.gov/ ) were screened for genes that were expressed differentially in breast cancer and were closely related to a poor prognosis. Gene expressions were verified by quantitative real-time polymerase chain reaction, and genes were knocked down by a lentivirus-based system. Cell growth and motility were evaluated and in vivo nude mice were used to confirm the in vitro roles of genes. Markers of epithelial-to-mesenchymal transition and the associations of KIF11 with the classical cancer signaling pathways were detected by Western blot. Results A series of genes expressed differentially in patients with breast cancer. The prognosis associated with high KIF11 expression was poor, and the expression of KIF11 increased significantly in high stage and malignant tumor cells. Inhibiting KIF11 expression in lentivirus-suppressed cells revealed that KIF11 inhibition significantly reduced cell viability and colony formation, inhibited migration and invasion, but promoted apoptosis. The sizes and weights of KIF11-inhibited tumors in nude mice were significantly lower than in the negative controls. Western blot showed that E-cadherin in breast cancer was significantly upregulated in KIF-inhibited cells and tumor tissues, whereas N-cadherin and vimentin were significantly downregulated. BT549 and MDA231 cells with KIF11 knockdown exhibited decreased ERK, AMPK, AKT, and CREB phosphorylation. Conclusion KIF11 acts as a potential oncogene that regulates the development and progression of breast cancer.

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“…Recently, it has been shown that rK858 induces apoptosis and reverses the malignant invasive phenotype in human glioblastoma cells [24] and also influences survivin-related chemoresistance in breast cancer cells [25]. While the anti-Eg5 and anti-tumour activities of rK858 have been characterised in cell-based assays and in vivo, the biochemical and structural basis for inhibiting Eg5 not only by rK858, but also for the other two thiadiazole containing derivatives (S)-ARRY-520 and (R)-Litronesib, are still unknown.…”

Section: Introductionmentioning

confidence: 99%

Crystal structure of the Eg5 - K858 complex and implications for structure-based design of thiadiazole-containing inhibitors

Talapatra

Tham

Guglielmi

et al. 2018

European Journal of Medicinal Chemistry

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The thiadiazole scaffold is an important core moiety in a variety of clinical drug candidates targeting a range of diseases. For example, the 2,4,5-substituted 1,3,4-thiadiazole scaffold is present in a lead compound and at least two clinical candidates targeting the human motor protein Eg5, against neoplastic diseases. An inhibitor named K858 has in vivo activity in various mouse xenografts whereas the clinical candidates (S)-ARRY-520 and (R)-Litronesib have entered clinical trials with the former one in phase III clinical trials either alone or in combination with a proteasome inhibitor against relapsed/refractory multiple myeloma. Astonishingly, structural data are lacking for all thiadiazole-containing Eg5 inhibitors. Here we report the structure determination of two crystal forms of the ternary Eg5-ADP-K858 complex, locking the motor in the so-called final inhibitor bound state, thus blocking ADP release, a crucial stage for Eg5 activity. K858 acts at the established allosteric inhibitor-binding pocket formed of helix α2, loop L5 and helix α3. The structure of the complex has far reaching consequences for thiadiazole containing Eg5 inhibitors. For example, we could rationalise the structure-activity relationship in the crucial 5-position of the thiadiazole scaffold and the complex will serve in the future as a basis for strucutre-based drug design.

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The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells

Cited by 22 publications

References 33 publications

Resistance to the mTOR inhibitor everolimus is reversed by the downregulation of survivin in breast cancer cells

Resistance to the mTOR inhibitor everolimus is reversed by the downregulation of survivin in breast cancer cells

KIF11 Functions as an Oncogene and Is Associated with Poor Outcomes from Breast Cancer

Crystal structure of the Eg5 - K858 complex and implications for structure-based design of thiadiazole-containing inhibitors

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