Purvalanol A is a strong apoptotic inducer via activating polyamine catabolic pathway in MCF-7 estrogen receptor positive breast cancer cells

Obakan, Pinar; Arısan, Elif Damla; Ozfiliz, Pelin; Gürkan, Ajda Çoker; Palavan-Ünsal, Narçın

doi:10.1007/s11033-013-2847-1

Cited by 14 publications

(14 citation statements)

References 29 publications

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“…In our previous study, we determined that 30 µM purvalanol induced apoptotic cell death by modulating the expression of the Bcl-2 family members via activating polyamine catabolic metabolism in HCT 116 colon cancer cells (7). Another previous study from our laboratory showed that 25 µM purvalanol induced apoptosis via activation of caspases, which led to dysfunction of MMP in MCF-7 breast cancer cells (6). A lower dose of purvalanol (15 µM) used in this study also inhibited cell proliferation via cell cycle arrest and induced cell death through MMP loss figure 5.…”

Section: Discussionmentioning

confidence: 97%

“…Intracellular polyamine levels are under the control of several catabolic enzymes, such as spermidine/spermine-N-acetyl transferase (SSAT). Although purvalanol-induced cell cycle arrest and apoptotic cell death were demonstrated in prostate (5), breast (6) and colon cancer cells (7), the exact molecular mechanism of purvanol-induced apoptosis has not been elucidated yet.…”

Section: Introductionmentioning

confidence: 99%

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Purvalanol induces endoplasmic reticulum stress-mediated apoptosis and autophagy in a time-dependent manner in HCT116 colon cancer cells

et al. 2015

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Purvalanol, a novel cyclin-dependent kinase inhibitor, is referred to as a strong apoptotic inducer which causes cell cycle arrest in various cancer cells such as prostate, breast and colon cancer cell lines. Various physiological and pathological conditions such as glucose starvation, inhibition of protein glycosylation and oxidative stress may cause an accumulation of unfolded proteins in the endoplasmic reticulum (ER), leading to the unfolded protein response (UPR) and autophagy. Lacking proteosomal function on aggregates of unfolded proteins, ER stress may induce autophagic machinery. Autophagy, an evolutionarily conserved process, is characterized by massive degradation of cytosolic contents. In the present study, our aim was to determine the time-dependent, ER-mediated apoptotic and autophagy induction of purvalanol in HCT 116 colon cancer cells. Fifteen micromoles of purvalanol induced a reduction in cell viability by 20 and 35% within 24 and 48 h, respectively. HCT 116 colon cancer cells were exposed to purvalanol, which activated ER stress via upregulation of PERK, IRE1α gene expression, eIF-2α phosphorylation and ATF-6 cleavage at early time-points in the HCT 116 colon cancer cells. Moreover, we determined that during purvalanol-mediated ER stress, autophagic machinery was also activated prior to apoptotic cell death finalization. Beclin-1 and Atg-5 expression levels were upregulated and LC3 was cleaved after a 6 h purvalanol treatment. Purvalanol induced mitochondrial membrane potential loss, caspase-7 and caspase-3 activation and PARP cleavage following a 48 h treatment. Thus, we conclude that the anticancer effect of purvalanol in HCT 116 cells was due to ER stress-mediated apoptosis; however, purvalanol triggered autophagy, which functions as a cell survival mechanism at early time-points.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Purvalanol induces endoplasmic reticulum stress-mediated apoptosis and autophagy in a time-dependent manner in HCT116 colon cancer cells

et al. 2015

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“…Roscovitine is a new-generation CDK inhibitor that induces apoptosis via blocking the cell cycle at G 1 /S and G 2 /M checkpoints through activation of caspases and cytochrome-c release (Henfling et al, 2004). In vitro studies showed that roscovitine is a promising therapeutic agent in prostate (Arisan et al, 2014), leukemia (Hahntow et al, 2004), and breast (Obakan et al, 2014) cancer. Moreover, roscovitine has been shown to induce cell cycle arrest and apoptosis in ER-MDA-MB-231 breast cancer cells (Mgbonyebi et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of c-Myc mediated ODC expression after purvalanol treatment is under control of upstream MAPK signaling axis in MCF-7 breast cancer cells

Obakan¹,

Alkurt²,

Köse³

et al. 2014

Turk J Biol

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IntroductionMammalian cell division, mitotic transfer of genome to new daughter cells, occurs when the cell has enough cytoplasmic content and DNA replication is finished correctly. The regulatory mechanisms during interphase (G1, S, G2 phases) control the cell division decision by the presence of various time-dependent and regularly activated molecules such as cyclin and cyclin-dependent kinases (CDKs) (Morgan et al., 1998). Each interphase phase has its own activated cyclin-CDK complexes that permit cell cycle progression during surveillance mechanisms (Arellano et al., 1997). Growth promoting signals due to growth factors change the cell cycle regulation and promote neoplastic transformation (Paulovich et al., 1997). Recently, new approaches to antineoplastic therapy are focused on cyclin-CDK complex inhibition.Thus far, 6 classes of chemical CDK inhibitors have been characterized, including purine-derived CDK inhibitors (Meijer, 1996). Olomoucine, roscovitine, and purvalanol are the most commonly investigated CDK inhibitors that cause cell cycle arrest and trigger apoptotic cell death. Roscovitine (CYC202, Seliciclib) or purvalanol induce apoptosis by causing cell cycle arrest in the G1 and G2/M phases in prostate (Ringer et al., 2010), lung (Zhang et al., 2010, multiple myeloma (Komina et al., 2011), colon, and breast cancer cell lines (Wesierska-Gadek et al., 2004;Arisan et al., 2012). Although CDK inhibitor-induced apoptotic cell death has been determined in breast cancer, the exact underlying molecular targets in cell death and survival mechanism have not been clarified yet.MAPKs are regulated by various cellular arrangements such as cell growth, differentiation, and apoptotic cell Abstract: Roscovitine and purvalanol are specific cyclin-dependent kinase (CDK) inhibitors, which induce apoptosis by triggering cell cycle arrest in various cancer cells such as colon, prostate, and breast cancer cells. Although the apoptotic action of roscovitine was clarified at the molecular level, the exact mechanism of purvalanol-induced apoptosis is still under investigation. The mitogenactivated protein kinase (MAPK) signaling cascade is activated by different inducers related to growth, proliferation, differentiation processes, or environmental stress factors. Recent reports showed that modulation of MAPKs might lead to regulation of c-Myc, which is a transcription factor for the polyamine (PA) biosynthesis enzyme, ornithine decarboxylase (ODC). PAs are amine-derived cationic molecules that play crucial roles in cell proliferation, growth, and differentiation. In this study, we investigated the potential role of the MAPK signaling cascade in the purvalanol-induced apoptosis mechanism by comparing the results of roscovitine in MCF-7 and MDA-MB-231 breast cancer cells. We found that CDK inhibitors decreased the cell viability in a dose-and time-dependent manner in MCF-7 and MDA-MB-231 cancer cells. Although both CDK inhibitors induced cell cycle arrest, which led to apoptosis by activating caspases and PARP cleavage in ...

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“…As shown in our recent study with endoxifen and by other studies, SMO induction is a remarkable chemotherapeutic target [ 36 , 71 , 72 , 73 ]. Purvalanol, a specific CDK inhibitor with apoptosis inducing activity in breast cancer cells, also induced SSAT, APAO and SMO in MCF-7 and MDA-MB-231 breast cancer cells [ 74 ]. Cervelli et al [ 43 ] analyzed SMO mRNA and enzyme activity in breast cancer tissues and non-tumor samples.…”

Section: Polyamine Analogues and Breast Cancer Therapeuticsmentioning

confidence: 99%

Cellular and Animal Model Studies on the Growth Inhibitory Effects of Polyamine Analogues on Breast Cancer

Thomas

2018

Medical Sciences

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Polyamine levels are elevated in breast tumors compared to those of adjacent normal tissues. The female sex hormone, estrogen is implicated in the origin and progression of breast cancer. Estrogens stimulate and antiestrogens suppress the expression of polyamine biosynthetic enzyme, ornithine decarboxylate (ODC). Using several bis(ethyl)spermine analogues, we found that these analogues inhibited the proliferation of estrogen receptor-positive and estrogen receptor negative breast cancer cells in culture. There was structure-activity relationship in the efficacy of these compounds in suppressing cell growth. The activity of ODC was inhibited by these compounds, whereas the activity of the catabolizing enzyme, spermidine/spermine N1-acetyl transferase (SSAT) was increased by 6-fold by bis(ethyl)norspermine in MCF-7 cells. In a transgenic mouse model of breast cancer, bis(ethyl)norspermine reduced the formation and growth of spontaneous mammary tumor. Recent studies indicate that induction of polyamine catabolic enzymes SSAT and spermine oxidase (SMO) play key roles in the anti-proliferative and apoptotic effects of polyamine analogues and their combinations with chemotherapeutic agents such as 5-fluorouracil (5-FU) and paclitaxel. Thus, polyamine catabolic enzymes might be important therapeutic targets and markers of sensitivity in utilizing polyamine analogues in combination with other therapeutic agents.

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Purvalanol A is a strong apoptotic inducer via activating polyamine catabolic pathway in MCF-7 estrogen receptor positive breast cancer cells

Cited by 14 publications

References 29 publications

Purvalanol induces endoplasmic reticulum stress-mediated apoptosis and autophagy in a time-dependent manner in HCT116 colon cancer cells

Purvalanol induces endoplasmic reticulum stress-mediated apoptosis and autophagy in a time-dependent manner in HCT116 colon cancer cells

Downregulation of c-Myc mediated ODC expression after purvalanol treatment is under control of upstream MAPK signaling axis in MCF-7 breast cancer cells

Cellular and Animal Model Studies on the Growth Inhibitory Effects of Polyamine Analogues on Breast Cancer

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