T-type Ca2+ channel blocker, KYS05047 induces G1 phase cell cycle arrest by decreasing intracellular Ca2+ levels in human lung adenocarcinoma A549 cells

Rim, Hong-Kun; Lee, Heon-Woo; Choi, In-Chan; Park, Jin Yeong; Choi, Heung Woo; Choi, Jung‐Hye; Cho, Young-Wuk; Lee, Jae Yeol; Lee, Kyung‐Tae

doi:10.1016/j.bmcl.2012.09.076

Cited by 28 publications

(14 citation statements)

References 25 publications

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“…Therefore, VGCCs blockers could represent a promising tool for anticancer therapy (38,39). In fact, consistent with the observation that Ca þþ entry activates Akt/PKB in a PI3K-independent manner in neuroblastoma cells (40), T-type calcium channels inhibition was reported to interfere with mTOR/AKT pathway in human lung adenocarcinoma cells (41) and to disrupt Akt signaling, promoting apoptosis, in glioblastoma cells (42). Nevertheless, VGCCs blockers have also been reported to activate Akt, increasing GSK3 inhibitory phosphorylation (43), as well as to cause GSK3 dephosphorylation in several cell culture systems (44).…”

Section: Discussionsupporting

confidence: 68%

FoxO3a Mediates the Inhibitory Effects of the Antiepileptic Drug Lamotrigine on Breast Cancer Growth

Pellegrino

Rizza

Nigro

et al. 2018

Molecular Cancer Research

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Breast cancer is a complex and heterogeneous disease, with distinct histologic features dictating the therapy. Although the clinical outcome of breast cancer patients has been considerably improved, the occurrence of resistance to common endocrine and chemotherapy treatments remains the major cause of relapse and mortality. Thus, efforts in identifying new molecules to be employed in breast cancer therapy are needed. As a "faster" alternative to reach this aim, we evaluated whether lamotrigine, a broadly used anticonvulsant, could be "repurposed" as an antitumoral drug in breast cancer. Our data show that lamotrigine inhibits the proliferation, the anchorage-dependent, and independent cell growth in breast cancer cells (BCC), including hormone-resistant cell models. These effects were associated with cell-cycle arrest and modulation of related proteins (cyclin D1, cyclin E, p27, and p21), all target genes of FoxO3a, an ubiquitous transcription factor negatively regulated by AKT. Lamotrigine also increases the expression of another FoxO3a target, PTEN, which, in turn, downregulates the PI3K/Akt signaling pathway, with consequent dephosphorylation, thus activation, of FoxO3a. Moreover, lamotrigine induces FoxO3a expression by increasing its transcription through FoxO3a recruitment on specific FHRE located on its own promoter, in an autoregulatory fashion. Finally, lamotrigine significantly reduced tumor growth , increasing FoxO3a expression. The anticonvulsant drug lamotrigine shows strong antiproliferative activity on breast cancer, both and Thus, drug repurposing could represent a valuable option for a molecularly targeted therapy in breast cancer patients. .

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Section: Discussionsupporting

confidence: 68%

FoxO3a Mediates the Inhibitory Effects of the Antiepileptic Drug Lamotrigine on Breast Cancer Growth

Pellegrino

Rizza

Nigro

et al. 2018

Molecular Cancer Research

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“…They appear to be a contributor to abnormal growth of ventricular cells (Martínez et al, 1999) and may dispose hypertrophic tissue to arrhythmias (Nuss and Houser, 1993). Finally, there is accumulating evidence that T-type calcium channels may also participate in the growth of certain cancers (Ohkubo and Yamazaki, 2012;Rim et al, 2012;Zhang et al, 2012;Das et al, 2013;Gackière et al, 2013;Dziegielewska et al, 2014).…”

Section: Ca V 3 Channel Pathophysiologymentioning

confidence: 99%

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

Zamponi¹,

Striessnig²,

Koschak³

et al. 2015

Pharmacol Rev

866

992

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“…Because of these properties, T-type calcium channels have been described as being “ideally suited for regulating neuronal excitability” (Iftinca, 2011). Currently, T-type calcium channel blockers are found to be ameliorative for a variety of conditions including epilepsy, essential tremor, and neuropathic pain, and the roles these channels play in autism, vasodilation, sleep cycle regulation, and tumor cell cycle regulation continue to be investigated (Anderson et al, 2005; Astori et al, 2011; Brodie et al, 2012; Dogrul et al, 2003; Oshima et al, 2005; Quesada et al, 2011; Rim et al, 2012; Splawski et al, 2006). …”

Section: Introductionmentioning

confidence: 99%

Age-related downregulation of the CaV3.1 T-type calcium channel as a mediator of amyloid beta production

Rice¹,

Berchtold²,

Cotman³

et al. 2014

Neurobiology of Aging

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Alzheimer's is a crippling neurodegenerative disease that largely affects aged individuals. Decades of research have highlighted age-related changes in calcium homeostasis that occur before and throughout the duration of the disease, and the contributions of such dysregulation to Alzheimer's disease pathogenesis. We report an age-related decrease in expression of the CaV3.1 T-type calcium channel at the level of messenger RNA and protein in both humans and mice that is exacerbated with the presence of Alzheimer's disease. Downregulating T-type calcium channels in N2a cells and the 3xTg-AD mouse model of Alzheimer's disease, by way of pharmacologic inhibition with NNC-55-0396, results in a rapid increase in amyloid beta production via reductions in non-amyloidogenic processing, whereas genetic over-expression of the channel in human embryonic kidney cells expressing amyloid precursor protein produces complementary effects. The age-related decline in CaV3.1 expression may therefore contribute to a pro-amyloidogenic environment in the aging brain and represents a novel opportunity to intervene in the course of Alzheimer's disease pathogenesis.

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T-type Ca2+ channel blocker, KYS05047 induces G1 phase cell cycle arrest by decreasing intracellular Ca2+ levels in human lung adenocarcinoma A549 cells

Cited by 28 publications

References 25 publications

FoxO3a Mediates the Inhibitory Effects of the Antiepileptic Drug Lamotrigine on Breast Cancer Growth

FoxO3a Mediates the Inhibitory Effects of the Antiepileptic Drug Lamotrigine on Breast Cancer Growth

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

Age-related downregulation of the CaV3.1 T-type calcium channel as a mediator of amyloid beta production

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