Expression of Ca2+/calmodulin-dependent protein kinase types II and IV, and reduced DNA synthesis due to the Ca2+/calmodulin-dependent protein kinase inhibitor KN-62 (1-[N,O-Bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine) in small cell lung carcinoma

Williams, Carol L.; Phelps, Scott H.; Porter, Rebecca A.

doi:10.1016/s0006-2952(95)02393-3

Cited by 42 publications

(31 citation statements)

References 43 publications

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“…Furthermore, the deletion or inactivation of CaM kinase II has been shown to cause cell cycle arrest [Lu and Means, 1993]. KN-62, an inhibitor of CaM kinase II, potently inhibited DNA synthesis, slowed progression through S phase [Williams et al, 1996], and caused an accumulation of cells in S phase [Minami et al, 1994]. According to the present results, blockage of the cell cycle progression and S phase accumulation were observed only in male astrocytes.…”

Section: Discussionsupporting

confidence: 57%

Sexually Dimorphic Effect of Glutamate Treatment on Cell Cycle Arrestment of Astrocytes from the Preoptic Area of Neonatal Rats

Hsu

Hsieh

et al. 2001

Dev Neurosci

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Neurotoxicological studies have indicated that L-glutamate exhibits more pronounced effects on the preoptic area (POA) neurons of male rats than on those of females in the neonatal period. However, no information has previously been available as to whether or not such sexual dimorphism also exists for the effects of glutamate on astrocytes from POA. The present paper reports the differential effects of L-glutamate on astrocytes isolated from POA of neonatal male and female rats. The proliferation of astrocytes was measured by methods of cell count and cell cycle analysis. In addition, the activity of Ca²⁺/calmodulin-dependent protein kinase II (CaM kinase II) was assayed to understand its role in the glutamate-induced disturbance of the cell cycle progression of astrocytes. The results revealed that L-glutamate, at doses of 0.5 and 1.0 mM, inhibited the proliferation of astrocytes derived from male rats more severely than those derived from females. The L-glutamate treatment blocked the cell cycle progression and caused an accumulation of cells in the S phase. The activity of CaM kinase II declined more markedly in astrocytes derived from male rats than in those from females after glutamate treatment. These findings suggest that the proliferation of astrocytes derived from POA of neonatal rats can be inhibited in a sexually dimorphic manner by L-glutamate, possibly through blocking the cell cycle progression and partially related to the inactivation of the CaM kinase II.

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Section: Discussionsupporting

confidence: 57%

Sexually Dimorphic Effect of Glutamate Treatment on Cell Cycle Arrestment of Astrocytes from the Preoptic Area of Neonatal Rats

Hsu

Hsieh

et al. 2001

Dev Neurosci

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“…Naftopidil and RS100329 both possess a phenylpiperazine-based structure and arrest cells in G 1 . Interestingly, the Ca 2þ /calmodulin-dependent protein kinase (CaM kinase) inhibitor KN-62 has a phenylpiperazine structure and induces G 1 cell-cycle arrest in small cell lung carcinoma (SCLC) cells (23,24). In this study, the phenylpiperazine-derived, a 1D -selective antagonist BMY7378 did not induce G 1 cell-cycle arrest at low concentration (10 mmol/L; Fig.…”

Section: Discussionmentioning

confidence: 61%

Naftopidil, a Selective α1-Adrenoceptor Antagonist, Suppresses Human Prostate Tumor Growth by Altering Interactions between Tumor Cells and Stroma

Hori

Ishii

Kanda

et al. 2011

Cancer Prevention Research

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In prostate cancer, tumor-stroma interactions play a critical role in the promotion of tumorigenesis, and thus the prevention of those interactions is a promising target to suppress tumor growth. Several studies demonstrated that alpha 1 -adrenoceptor (a 1 -AR) antagonists, therapeutic drugs for benign prostatic hyperplasia, have growth inhibitory effects on human prostate cancer (PCa) cells through induction of apoptosis or G 1 cell-cycle arrest. However, their direct actions on stromal cells surrounding cancer cells have not yet been elucidated. In this study, we investigated the effects of subtype-selective a 1 -AR antagonists (naftopidil, tamsulosin, and silodosin) on prostate tumor growth with a focus on the role of stroma, using commercially available fibroblast cells (PrSC). Tumorigenic studies in vivo showed significant reductions in tumor growth when E9 cells (an androgen low-sensitive LNCaP subline) grafted with PrSC were treated with naftopidil. In in vitro analyses, naftopidil and silodosin showed antiproliferative effects on PCa cells regardless of androgen sensitivity and a 1 -AR subtype expression. In PrSC, a strong growth inhibitory effect was observed with naftopidil but not silodosin. Flow cytometric analysis revealed that naftopidil, but not silodosin, induced G 1 cell-cycle arrest in both PCa cells and PrSC. In naftopidil-treated PrSC, total interleukin-6 protein was significantly reduced with increased suppression of cell proliferation. Silodosin induced weak early apoptosis only in PCa cells. These findings demonstrated that naftopidil strongly suppressed cell proliferation of stromal cells, resulting in decreased tumorigenic soluble factor, suggesting that naftopidil might be effective in preventing stromal support of tumor cells.

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“…Based on previous literature implicating a positive effect of CaMKII in cell cycle control in other systems (17,45,49) and the observed correlation between increased expression of CaMKII␦ 2 and VSMC proliferation in culture, it is logical to hypothesize that this specific isoform is a potential link coupling Ca 2ϩ signals to VSMC growth. To suppress the expression of the CaMKII␦ 2 subunit, a siRNA sequence specifically targeting all CaMKII␦ subunits was designed and cloned in an adenoviral vector as a shRNA (shDELTA2).…”

Section: Resultsmentioning

confidence: 99%

“…Most previous studies have employed the use of pharmacological agents (45,49), which may have nonspecific cellular effects. In addition, these agents affect all CaMKII isoforms in the cell and therefore do not allow the functions of distinct CaMKII isoforms to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…CaMKII␦ 2 facilitates adhesion-dependent activation of ERK1/2 in cultured VSM through both integrin-dependent and -independent mechanisms (22) and has been shown to be involved in the regulation of cultured VSMC migration (35,36). CaMKII has been implicated in cell-cycle control in a number of systems, although most studies to date have relied on pharmacological inhibitors of CaMKII, such as KN-62 (49) and , or overexpression of constitutively active mutants (3,37). Recently, small-interfering RNA (siRNA) suppression of CaMKII␥ was reported to disrupt regulation of mitotic spindles in several human cell lines (17).…”

mentioning

confidence: 99%

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Calcium/calmodulin-dependent protein kinase II-δ isoform regulation of vascular smooth muscle cell proliferation

House¹,

Ginnan²,

Armstrong³

et al. 2007

American Journal of Physiology-Cell Physiology

107

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show abstract

Expression of Ca2+/calmodulin-dependent protein kinase types II and IV, and reduced DNA synthesis due to the Ca2+/calmodulin-dependent protein kinase inhibitor KN-62 (1-[N,O-Bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine) in small cell lung carcinoma

Cited by 42 publications

References 43 publications

Sexually Dimorphic Effect of Glutamate Treatment on Cell Cycle Arrestment of Astrocytes from the Preoptic Area of Neonatal Rats

Sexually Dimorphic Effect of Glutamate Treatment on Cell Cycle Arrestment of Astrocytes from the Preoptic Area of Neonatal Rats

Naftopidil, a Selective α1-Adrenoceptor Antagonist, Suppresses Human Prostate Tumor Growth by Altering Interactions between Tumor Cells and Stroma

Calcium/calmodulin-dependent protein kinase II-δ isoform regulation of vascular smooth muscle cell proliferation

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