Inhibition of human tumor cell growth <i>in vivo</i> by an orally bioavailable inhibitor of CDC25 phosphatases

Brezak, Marie‐Christine; Quaranta, Muriel; Contour-Galcéra, Marie-Odile; Lavergne, Olivier; Mondésert, Odile; Auvray, Pierrı̈ck; Kasprzyk, Philip G.; Prevost, Grégoire; Ducommun, Bernard

doi:10.1158/1535-7163.mct-05-0168

Cited by 61 publications

(45 citation statements)

References 29 publications

(26 reference statements)

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“…Initial results support the view that CDC25 is an interesting and important anticancer target, 12,13,23 and considerable effort is currently directed to the identification additional candidate drugs. Here, we describe a novel small molecule bearing two quinone moieties that is a potent inhibitor of CDC25 family members and which inhibits human tumor cell proliferation in both in vitro and in vivo models.…”

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confidence: 69%

“…IRC-083065 was initially coded as BN82685. 13 IRC-083864 is a dry powder freshly prepared in 30% HPB-cyclodextrin vehicle for intravenous dosing and in D5W for oral dosing. Paclitaxel (Natural Pharmaceuticals, Lot No.…”

Section: Preparation Of Irc-083864mentioning

confidence: 99%

“…[9][10][11][12][13][14][15][16][17][18][19][20][21][22] Several mechanisms of action have been proposed for these inhibitors such as oxidization of the catalytic site cysteine, Michael acceptors capable of reacting with the activated thiolate or other electrophilic entities. Initial results support the view that CDC25 is an interesting and important anticancer target, 12,13,23 and considerable effort is currently directed to the identification additional candidate drugs. Here, we describe a novel small molecule bearing two quinone moieties that is a potent inhibitor of CDC25 family members and which inhibits human tumor cell proliferation in both in vitro and in vivo models.…”

mentioning

confidence: 99%

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IRC‐083864, a novel bis quinone inhibitor of CDC25 phosphatases active against human cancer cells

Brezak

Valette

Quaranta

et al. 2008

Intl Journal of Cancer

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CDC25 phosphatases are key actors in cyclin-dependent kinases activation whose role is essential at various stages of the cell cycle. CDC25 expression is upregulated in a number of human cancers. CDC25 phosphatases are therefore thought to represent promising novel targets in cancer therapy. Here, we report the identification and the characterization of IRC-083864, an original bis-quinone moiety that is a potent and selective inhibitor of CDC25 phosphatases in the low nanomolar range. IRC-083864 inhibits cell proliferation of a number of cell lines, regardless of their resistance to other drugs. It irreversibly inhibits cell proliferation and cell cycle progression and prevents entry into mitosis. In addition, it inhibits the growth of HCT-116 tumor spheroids with induction of p21 and apoptosis. Finally, IRC-083864 reduced tumor growth in mice with established human prostatic and pancreatic tumor xenografts. This study describes a novel compound, which merits further study as a potential anticancer agent. ' 2008 Wiley-Liss, Inc.Key words: CDC25 phosphatase; cell cycle; cancer; pharmacology CDC25 phosphatases dephosphorylate and hence, activate cyclin-dependent kinases (CDKs), thus participating as major actors in the control of cell cycle progression. Their function is also tightly linked to the maintenance of genomic integrity as targets of the checkpoint machinery activated upon DNA injury. 1During the past decade, an increasing body of evidence suggests that CDC25 phosphatases are key players in cell transformation and in cancer progression.2 For instance, when specifically targeted to the mammary gland, overexpression of CDC25B, in association with the carcinogen DMBA (9,10-dimethyl-1,2-benzanthracene), has been shown to induce neoplasia. 3,4 Further, hemizygous disruption of CDC25A inhibits cellular transformation and mammary tumorigenesis in mice, suggesting that a low level of CDC25A protein plays a rate-limiting role in transformation and tumor initiation mediated by oncogene such as H-ras 12 and neu. 5,6 Finally, overexpression of CDC25A and CDC25B proteins has been observed in a wide variety of human tumors (see ref. 2 and 7 for review), and these observations have often been linked to a poor prognosis, suggesting an important role in tumor behavior.A limited number of small molecule inhibitors of the CDC25 phosphatases have been identified (see ref. 1,8 for review), but little is known about either their metabolism or efficacy in xenograft tumor models. These compounds are mainly quinones but also phosphate surrogates or electrophilic entities.9-22 Several mechanisms of action have been proposed for these inhibitors such as oxidization of the catalytic site cysteine, Michael acceptors capable of reacting with the activated thiolate or other electrophilic entities. Initial results support the view that CDC25 is an interesting and important anticancer target, 12,13,23 and considerable effort is currently directed to the identification additional candidate drugs. Here, we describe a novel small molecule...

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confidence: 69%

Section: Preparation Of Irc-083864mentioning

confidence: 99%

mentioning

confidence: 99%

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IRC‐083864, a novel bis quinone inhibitor of CDC25 phosphatases active against human cancer cells

Brezak

Valette

Quaranta

et al. 2008

Intl Journal of Cancer

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“…In an attempt to further investigate the mechanism by which leukemia cell lines are able to recover from the DNA-damage cell cycle checkpoint in G2, we performed similar experiments to that described in Figure 1a in the presence of the BN82685 compound, a previously described selective chemical inhibitor of CDC25 phosphatases (Brezak et al, 2005). We found that treatment with VP-16 and BN82685 led to a significant decrease in the percentage of mitotic cells over time in the U937 and KG1a cultures and that this occurred in a BN82685 dose-dependent manner (Figures 2a and b), indicating that mitotic entry was impaired following the inhibition of all CDC25 phosphatases.…”

Section: Cdc25b Plays a Role In G2/m Checkpoint Recoverymentioning

confidence: 99%

G2/M checkpoint stringency is a key parameter in the sensitivity of AML cells to genotoxic stress

et al. 2008

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Acute myeloid leukemia (AML) cells exposed to genotoxic agents arrest their cell cycle at the G2/M checkpoint and are inherently chemoresistant. To understand the mechanism of this chemoresistance, we compared the ability of immature CD34 þ versus mature CD34À AML cell lines (KG1a and U937, respectively) to recover from a DNA damage-induced cell cycle checkpoint in G2. Here, we report that KG1a cells have a more stringent G2/M checkpoint response than U937 cells. We show that in both cell types, the CDC25B phosphatase participates in the G2/M checkpoint recovery and that its expression is upregulated. Furthermore, we show that CHK1 inhibition by UCN-01 in immature KG1a cells allows checkpoint exit and induces sensitivity to genotoxic agents. Similarly, UCN-01 treatment potentializes genotoxic-induced inhibition of colony formation efficiency of primary leukemic cells from AML patients. Altogether, our results demonstrate that checkpoint stringency varies during the maturation process and indicate that targeting checkpoint mechanisms might represent an attractive therapeutic opportunity for chemoresistant immature AML cells.

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“…Then, the reaction mixture was diluted to a final concentration of 0.1 μM at which the inhibitors are inactive (data not shown). If the inhibitory effects persist after dilution, the mechanism of action should be considered as irreversible (21). As indicated in Fig.…”

Section: Resultsmentioning

confidence: 99%

Antiproliferative effect of natural tetrasulfides in human breast cancer cells is mediated through the inhibition of the cell division cycle 25 phosphatases

Viry¹,

Ali²,

Kirsch³

et al. 2011

Int J Oncol

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Abstract. For many years, in vitro and in vivo studies have reported that organosulfur compounds (OSCs), naturally found in Allium vegetables, are able to suppress the proliferation of various tumor cells. In spite of recent advances, the specific molecular mechanisms involved in OSC activity are still unclear. Considering the antiproliferative effects observed in cancer cells, we postulated that OSCs might target the cell division cycle (Cdc) 25 phosphatases which are crucial enzymes of the cell cycle. Our findings suggest phosphatases Cdc25 as possible targets of naturally occuring polysulfides contributing to their anticancer properties. We report on the inhibitory activity of tetrasulfides occurring naturally in garlic and onion towards the human Cdc25 phosphatases. Diallyl-and dipropyltetrasulfides have emerged as interesting irreversible inhibitors of the Cdc25 isoforms A and C in vitro. Furthermore, growth of both sensitive (MCF-7) and resistant (Vcr-R) human breast carcinoma cells was significantly decreased by these tetrasulfides. The observed antiproliferative effect appeared to be associated with a G 2 -M cell cycle arrest.

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Inhibition of human tumor cell growth in vivo by an orally bioavailable inhibitor of CDC25 phosphatases

Cited by 61 publications

References 29 publications

IRC‐083864, a novel bis quinone inhibitor of CDC25 phosphatases active against human cancer cells

IRC‐083864, a novel bis quinone inhibitor of CDC25 phosphatases active against human cancer cells

G2/M checkpoint stringency is a key parameter in the sensitivity of AML cells to genotoxic stress

Antiproliferative effect of natural tetrasulfides in human breast cancer cells is mediated through the inhibition of the cell division cycle 25 phosphatases

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