Glycogen synthase kinase 3β inhibition sensitizes pancreatic cancer cells to gemcitabine

Shimasaki, Takeo; Ishigaki, Yasuhito; Nakamura, Yuka; Takata, Takanobu; Nakaya, Naoki; Nakajima, Hideo; Sato, Itaru; Zhao, Xia; Kitano, Ayako; Kawakami, Kazuyuki; Tanaka, Takuji; Takegami, Tsutomu; Tomosugi, Naohisa; Minamoto, Toshinari; Motoo, Yoshiharu

doi:10.1007/s00535-011-0484-9

Cited by 51 publications

(60 citation statements)

References 46 publications

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“…A number of in vivo studies have investigated the antitumor activity of distinct GSK-3 inhibitors in a variety of cancer cell line-derived tumor xenograft models [14,21,22,24,33,39,40]. These studies utilized toolkit GSK-3 inhibitors as monotherapies.…”

Section: Discussionmentioning

confidence: 99%

GSK-3 inhibition overcomes chemoresistance in human breast cancer

et al. 2016

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Glycogen Synthase Kinase-3β (GSK-3β), a serine/threonine protein kinase, is an emerging therapeutic target in the treatment of human breast cancer. In this study, we demonstrate that the pharmacological inhibition of GSK-3 by two novel small molecule GSK-3 inhibitors, 9-ING-41 and 9-ING-87, reduced the viability of breast cancer cells but had little effect on non-tumorigenic cell growth. Moreover, treatment with 9-ING-41 enhanced the antitumor effect of irinotecan (CPT-11) against breast cancer cells in vitro. We next established two patient-derived xenograft tumor models (BC-1 and BC-2) from metastatic pleural effusions obtained from patients with progressive, chemorefractory breast cancer and demonstrated that 9-ING-41 also potentiated the effect of the chemotherapeutic drug CPT-11 in vivo, leading to regression of established BC-1 and BC-2 tumors in mice. Our results suggest that the inhibition of GSK-3 is a promising therapeutic approach to overcome chemoresistance in human breast cancer, and identify the GSK-3 inhibitor 9-ING-41 as a candidate targeted agent for metastatic breast cancer therapy.

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Section: Discussionmentioning

confidence: 99%

GSK-3 inhibition overcomes chemoresistance in human breast cancer

et al. 2016

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“…Indeed, several studies have found that GSK3β inhibition reduces cell proliferation, increases cell apoptosis and sensitizes cells to death by different stimuli (Table 1) [26,38,39]. These phenotypes resulting from GSK3β inhibition are attributable to a variety of mechanisms including disruption of NF-κB-mediated survival [26,40] activation of tumor suppressors (p53 and Rb) [41], increased expression of the proapoptotic factor Bim [42], and inhibition of human telomerase reverse transcriptase and telomerase [35].…”

Section: Introductionmentioning

confidence: 99%

“…GSK3β inhibition by the small molecule AR-A014418 sensitized pancreatic cancer cells to apoptosis induced by TRAIL (tumor necrosis factor-related apoptosis inducing ligand) both in vitro and in tumor xenografts [38]. In addition, AR-A014418 was shown to sensitize the Panc-1 pancreatic cell line model to gemcitabine both in vitro and in vivo [36,39]. The role of GSK3β in chemotherapy resistance, however, is controversial, as Mamaghani et al [43] reported an overall lack of synergy and in some cases even antagonism between GSK3β inhibition (by AR-A014418) and gemcitabine in a panel of 6 pancreatic cancer cell lines.…”

Section: Introductionmentioning

confidence: 99%

Glycogen Synthase Kinase 3β in Pancreatic Cancer and its Implications in Chemotherapy and Radiation Therapy

et al. 2013

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Pancreatic cancer is a highly lethal disease with a poor prognosis characterized by local and systemic disease progression. Both radiation and chemotherapy play important roles in the management of this disease. However, in order to improve standard therapy many molecularly targeted agents are being developed. Glycogen synthase kinase 3β (GSK3β) participates in a multitude of cellular processes and is a newly proposed therapeutic target in pancreatic cancer. This review will discuss both the oncogenic and tumor suppressor functions of GSK3β in pancreatic cancer with an emphasis on the roles of GSK3β in tumor cell survival and sensitivity to radiation and chemotherapy.

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“…The effects of combination of AR-A014418 and gemcitabine were determined to be synergistic. One of the genes implicated in the response was the altered expression of p53-induced nuclear protein 1 which is a gene involved in regulating cell death and DNA repair(Shimasaki et al, 2012).The GSK-3 inhibitor lithium induces the ubiquitin-dependent proteasomal degradation of the downstream component of the HH signaling pathway glioma-associated oncogene homologue (GLI1). Lithium induced apoptosis and suppressed the tumorigenic potential of pancreatic cancer cells.…”

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confidence: 99%