Inhibition of G1/S transition potentiates oxaliplatin-induced cell death in colon cancer cell lines

Rakitina, Tatiana V.; Vasilevskaya, Irina A.; O’Dwyer, Peter J.

doi:10.1016/j.bcp.2007.01.037

Cited by 34 publications

(32 citation statements)

References 27 publications

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“…Because oxaliplatin is now widely used for Targeting Hsp90 for Therapy of Colon Cancer multimodality regimens in treating advanced or metastatic (liver) colorectal cancer, we focused on investigating the effects of 17-DMAG in combination with oxaliplatin on p53-wt and p53-deficient colon cancer cells. This aspect has, in part, been addressed in a recent study by Rakitina et al (29), showing that the geldanamycin derivate 17-AAG could prevent S-phase accumulation (G 1 -S transition), which is induced by oxaliplatin in p53-deficient colon cancer cells (HT29), thereby improving apoptotic effects by 17-AAG in vitro. In an earlier study, authors similarly used a cell death detection ELISA to detect effects of Hsp90 inhibition with or without addition of oxaliplatin on colon cancer cell apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that Hsp90 inhibitors promote oxaliplatin-dependent caspase activation and cytotoxicity by down-regulating antiapoptotic signaling through the transcription factor nuclear factor nB in colon cancer cell lines (28). Moreover, a recent study showed that Hsp90 inhibitors harbor the potential to inhibit G 1 -S transition in p53-deficient colon cancer cells, thereby enhancing cell cycle effects of oxaliplatin (29). Hence, we sought to investigate whether these solely in vitro results indeed translate into improved antineoplastic efficacy when combining oxaliplatin with Hsp90 inhibitors for treating colon cancer growth in vivo, as suggested by these authors.…”

Section: Effect Of Hsp90 Inhibition On Susceptibility Of Colon Cancermentioning

confidence: 94%

“…This crucial aspect has not been investigated for colon cancer and associated hepatic metastases. In favor of a Hsp90-based approach is evidence that Hsp90 inhibition may overcome resistance of p53-deficient colon cancer cells to oxaliplatin through prevention of S-phase accumulation, thus leading to additive or synergistic apoptotic effects in vitro (28,29). However, this hypothesis has not yet been validated in in vivo models.…”

Section: Introductionmentioning

confidence: 99%

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Blocking heat shock protein-90 inhibits the invasive properties and hepatic growth of human colon cancer cells and improves the efficacy of oxaliplatin in p53-deficient colon cancer tumors in vivo

Moser¹,

Lang²,

Kainz³

et al. 2007

Molecular Cancer Therapeutics

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We recently showed that inhibition of heat shock protein 90 (Hsp90) decreases tumor growth and angiogenesis in gastric cancer through interference with oncogenic signaling pathways. However, controversy still exists about the antimetastatic potential of Hsp90 inhibitors. Moreover, in vitro studies suggested that blocking Hsp90 could overcome p53-mediated resistance of cancer cells to oxaliplatin. We therefore hypothesized that blocking oncogenic signaling with a Hsp90 inhibitor would impair metastatic behavior of colon cancer cells and also improve the efficacy of oxaliplatin in vivo. Human colon cancer cells (HCT116, HT29, and SW620) and the Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) were used for experiments. In vitro, 17-DMAG substantially inhibited phosphorylation of epidermal growth factor receptor, c-Met, and focal adhesion kinase, overall resulting in a significant decrease in cancer cell invasiveness. Importantly, 17-DMAG led to an up-regulation of the transcription factor activating transcription factor-3, a tumor suppressor and antimetastatic factor, on mRNA and protein levels. In a cell death ELISA, 17-DMAG markedly induced apoptosis in both p53-wt and p53-deficient cells. In vivo, 17-DMAG significantly reduced tumor growth and vascularization. Furthermore, blocking Hsp90 reduced hepatic tumor burden and metastatic nodules in an experimental model of hepatic colon cancer growth. Importantly, combining oxaliplatin with 17-DMAG in vivo significantly improved growth inhibitory and proapoptotic effects on p53-deficient cells, compared with either substance alone. In conclusion, inhibition of Hsp90 abrogates the invasive properties of colon cancer cells and modulates the expression of the antimetastatic factor activating transcription factor-3. Hence, targeting Hsp90 could prove valuable for treatment of advanced colorectal cancer by effectively inhibiting colon cancer growth and hepatic metastasis and improving the efficacy of oxaliplatin.

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Section: Discussionmentioning

confidence: 99%

Section: Effect Of Hsp90 Inhibition On Susceptibility Of Colon Cancermentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Blocking heat shock protein-90 inhibits the invasive properties and hepatic growth of human colon cancer cells and improves the efficacy of oxaliplatin in p53-deficient colon cancer tumors in vivo

Moser¹,

Lang²,

Kainz³

et al. 2007

Molecular Cancer Therapeutics

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“…These results indicate that SNX-2112 can inhibit B16 cell growth via a mechanism involving G0/G1 arrest. It is possible that the Hsp90 client protein p53 may play a key role in the cell cycle distribution in B16 cells (20). As reported, 17-AAG induced G(0/1) cell cycle arrest and apoptosis in a dose-and time-dependent manner in mantle cell lymphoma cell lines by depleting levels of cyclin D1, Akt, Bid and activating caspase 9 (21).…”

Section: Discussionmentioning

confidence: 66%

The heat shock protein 90 inhibitor SNX-2112 inhibits B16 melanoma cell growth in vitro and in vivo

et al. 2012

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Abstract. SNX-2112 is a selective heat shock protein 90 (Hsp90) inhibitor which can exert a potent anticancer activity. In this study, we investigated the effects of SNX-2112 on B16 melanoma cells in vitro and in vivo. The 3-(4,5-dimetrylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis demonstrated that SNX-2112 dosedependently inhibited the growth of B16 cells, and induced G0/ G1 cell cycle arrest and apoptosis. Western blotting revealed that SNX-2112 lead to the degradation of Hsp90 client proteins including Akt, IKKα, NF-κB, B-Raf and GSK3β. Furthermore, we assessed the antitumor effect of SNX-2112 in vivo, using a xenograft model in C57BL/6 mice. Oral administration of SNX-2112 significantly inhibited the growth of B16 tumors in mice, with a 47% inhibition observed at dose of 80 mg/kg/day for 15 days, compared to control tumors. Hematoxylin-eosin (H&E) staining of xenograft tissues showed that SNX-2112 also inhibited angiogenesis and lead to a lower blood vessel density in the tumors, compared to the control group. These findings demonstrate that SNX-2112 can exhibit a potent anticancer activity against B16 melanoma cells both in vitro and in vivo, by inhibiting cell proliferation and inducing cell cycle arrest and apoptosis in a mechanism dependent on the degradation of Hsp90 client proteins. IntroductionHsp90 is an important ATP-dependent molecular chaperone required for protein folding, as well as the assembly and maintenance of the conformational stability of a diverse range of client proteins. Hsp90 client proteins play key roles in cellular metabolism, trafficking, signal transduction, chromatin remodeling, cell growth and differentiation (1-4). Hsp90 client proteins include cell survival and proliferation regulators, such as Akt, IKK, Raf, GSK3 and NF-κB (5-7). Hsp90 is overexpressed in tumor cells compared to their normal counterparts (8), and inhibition of Hsp90 has been considered as a possible strategy for the treatment of cancer.Currently, 14 drug candidates which target Hsp90 are undergoing clinical trials for multiple indications, either as single agents or in combination therapy, including 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504) and BIIB021 (9). 17-AAG was the first Hsp90 inhibitor to undergo phase III clinical trials, and is well tolerated and has a good therapeutic efficacy. However, 17-AAG has several potential limitations, including poor solubility, limited bioavailability and unsatisfactory hepatotoxicity (10-12). This has led to efforts to identify new, safer and more effective Hsp90 inhibitors for clinical applications.SNX-2112, a selective Hsp90 inhibitor, can bind to the N-terminal adenosine triphosphate binding site of Hsp90 and can exert significant growth inhibition of various cancer cell lines both in vitro and in vivo (13,14). In our previous research, SNX-2112 displayed promising anti-tumor activity in human chronic leukemia 16). In addition, SNX-2112 is ...

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“…From the present study, we report that the combination drug treatment selectively targets the MAP kinase signal transduction pathway. Several reports of 17AAG combination with oxaliplatin, flurouracil [25], carboplatin [26], paclitaxel [27], rapamycin [28], trastuzumab and tanespinycin [29], histone deacetylease [30] etc., suggests that 17AAG combination treatments not only enhance drug specific effects, but exhibit synergistic effects however not though MAP kinases. In a classical mitogen activated signaling pathway MEK binds to ERK and this coordinated binding is essential for the activation of ERK.…”

Section: Discussionmentioning

confidence: 99%

17-(Allylamino)-17-Demethoxygeldanamycin Combination with Curcumin Selectively Targets Mitogen Kinase Pathway in A Human Neuroblastoma Cell Line

Taiyab¹,

Usha²,

Amere³

2010

JCT

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Pharmacological inhibition of Hsp90 has emerged as a novel anticancer treatment. In this study we have investigated the effect of Hsp90 inhibitor drug 17AAG combination with curcumin on human neuroblastoma cells. The 17AAG treatment of cells for 18 h induced G1/S cell cycle arrest associated with cyclin D1 down regulation, and degradation of Raf-1 and inactivation of Akt. However, 17AAG treatment activated the mitogen kinase, ERK1, and induced the expression of stress proteins, Hsp70 and p53. The curcumin treatment resulted in G2/M cell cycle arrest and activation of both Raf1 and ERK1 kinases. The drugs in combination induced proteolytic degradation of Raf1 and Akt, and surpassed curcumin induced G2/M arrest. The combination treatment additionally inactivated MEK, inhibited activation and nuclear localization of ERK1, and also inhibited the stress protein induction. EGF stimulation induced re-activation of mitogen signaling with individual drug treatments but not in combination.This study highlights that 17AAG combination with curcumin selectively targets mitogen signal transduction mechanism through ERK1 inactivation. In conclusion, our study proposes the beneficial effects of 17AAG combination with curcumin in combating cancer.

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Inhibition of G1/S transition potentiates oxaliplatin-induced cell death in colon cancer cell lines

Cited by 34 publications

References 27 publications

Blocking heat shock protein-90 inhibits the invasive properties and hepatic growth of human colon cancer cells and improves the efficacy of oxaliplatin in p53-deficient colon cancer tumors in vivo

Blocking heat shock protein-90 inhibits the invasive properties and hepatic growth of human colon cancer cells and improves the efficacy of oxaliplatin in p53-deficient colon cancer tumors in vivo

The heat shock protein 90 inhibitor SNX-2112 inhibits B16 melanoma cell growth in vitro and in vivo

17-(Allylamino)-17-Demethoxygeldanamycin Combination with Curcumin Selectively Targets Mitogen Kinase Pathway in A Human Neuroblastoma Cell Line

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