Docetaxel in combination with octreotide shows synergistic apoptotic effect by increasing SSTR2 and SSTR5 expression levels in prostate and breast cancer cell lines

Karaca, Burçak; Degirmenci, Mustafa; Özveren, Ahmet; Atmaca, Harika; Bozkurt, Emir; Karabulut, Bülent; Şanlı, Ulus Ali; Uslu, Rüçhan

doi:10.1007/s00280-015-2756-1

Cited by 15 publications

(7 citation statements)

References 26 publications

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“…This study suggests that HDAC inhibitors may have an additional theranostic property in pulmonary carcinoids by increasing SSTR2 expression. As previously reported, there is evidence that the interaction of somatostatin and its’ analogs with somatostatin receptors has an antiproliferative action and can induce apoptosis, in addition to inhibiting tumorigenic hormone and growth factor secretion [8,9]. Furthermore, there is evidence that patients with low tumor SSTR expression have poor prognoses [15,25,26].…”

Section: Discussionmentioning

confidence: 99%

“…More recently, NET imaging using PET/CT with radiolabeled somatostatin analogs that specifically target somatostatin receptor subtype 2 (SSTR2) is becoming more standard as many NETs overexpress SSTR2 [4,5,6,7]. Indigenously, somatostatin is an anti-cancer neuropeptide, which is associated with the prevention of hormone and growth factor secretions that contribute to tumor growth, inhibition of tumor cell proliferation, and the induction of apoptosis mediated by the five different SST receptor subtypes (SSTR1-5) [8,9]. Clinically used somatostatin analogs have high affinities towards SSTR2, in addition to weaker affinities to SSTR3 and SSTR5 [10].…”

Section: Introductionmentioning

confidence: 99%

“…Most prominently, [ 68 Ga]DOTATATE binds to SSTR2 with an order of magnitude higher in affinity than other [ 68 Ga]-DOTA-peptides [10,11,12]. This suggests that a higher incidence and density of SSTR2 would be beneficial for imaging and treating patients [8]. However, only 34% TC, 71% of metastatic TC and 51% of AC showed a strong membrane presence of SSTR2.…”

Section: Introductionmentioning

confidence: 99%

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Pulmonary Carcinoid Surface Receptor Modulation Using Histone Deacetylase Inhibitors

Guenter

Aweda

Matos

et al. 2019

Cancers

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Pulmonary carcinoids are a type of neuroendocrine tumor (NET) accounting for 1–2% of lung cancer cases. Currently, Positron Emission Tomography (PET)/CT based on the radiolabeled sugar analogue [18F]-FDG is used to diagnose and stage pulmonary carcinoids, but is suboptimal due to low metabolic activity in these tumors. A new technique for pulmonary carcinoid imaging, using PET/CT with radiolabeled somatostatin analogs that specifically target somatostatin receptor subtype 2 (SSTR2), is becoming more standard, as many tumors overexpress SSTR2. However, pulmonary carcinoid patients with diminished SSTR2 expression are not eligible for this imaging or any type of SSTR2-specific treatment. We have found that histone deacetylase (HDAC) inhibitors can upregulate the expression of SSTR2 in pulmonary carcinoid cell lines. In this study, we used a non-cytotoxic dose of HDAC inhibitors to induce pulmonary carcinoid SSTR2 expression in which we confirmed in vitro and in vivo. A non-cytotoxic dose of the HDAC inhibitors: thailandepsin A (TDP-A), romidepsin (FK228), suberoylanilide hydroxamic acid (SAHA), AB3, and valproic acid (VPA) were administered to promote SSTR2 expression in pulmonary carcinoid cell lines and xenografts. This SSTR2 upregulation technique using HDAC inhibitors could enhance radiolabeled somatostatin analog-based imaging and the development of potential targeted treatments for pulmonary carcinoid patients with marginal or diminished SSTR2 expression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pulmonary Carcinoid Surface Receptor Modulation Using Histone Deacetylase Inhibitors

Guenter

Aweda

Matos

et al. 2019

Cancers

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“…As mentioned above, we demonstrated that octreotide suppresses apoptosis in the kidney after HIR. However, octreotide has been noted to induce apoptosis in different cancer cell lines in vitro 26 27 . This discrepancy may be due to different cell types, treatment factors, and experimental conditions etc.…”

Section: Discussionmentioning

confidence: 99%

Octreotide Attenuates Acute Kidney Injury after Hepatic Ischemia and Reperfusion by Enhancing Autophagy

Sun

Zou

Candiotti

et al. 2017

Sci Rep

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Octreotide exerts a protective effect in hepatic ischemia-reperfusion (HIR) injury. However, whether octreotide preconditioning could also reduce acute kidney injury (AKI) after HIR is unknown. This study was designed to investigate the role of octreotide in AKI after HIR. Male Sprague-Dawley rats were pretreated with octreotide or octreotide combined with 3-methyladenine (autophagy inhibitor, 3MA). Plasma creatinine, inflammation markers (e.g., TNF-α and IL-6 etc.), apoptosis, autophagy and phosphorylation of protein kinase B/mammalian target of rapamycin/p70 ribosomal S6 kinase (Akt/mTOR/p70S6K) in the kidney were measured after 60 minutes of liver ischemia and 24 hours of reperfusion for each rat. Octreotide pretreatment significantly preserved renal function and reduced the severity of renal injury. Moreover, octreotide alleviated inflammation and apoptosis in the kidney after HIR. Additionally, octreotide induced autophagy and autophagy inhibition with 3MA markedly reversed the renoprotective, anti-inflammatory and anti-apoptotic effects of octreotide after HIR. Finally, octreotide abrogated the activation of phosphorylation of Akt, mTOR and p70S6K in the kidney after HIR. Our results indicate that octreotide reduced renal injury after HIR due to its induction of autophagy. The enhancement of autophagy may be potentially linked to the octreotide mediated Akt/mTOR/p70S6K pathway deactivation and reduction of kidney inflammation and apoptosis after HIR.

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“…In spite of a similar binding affinity of SSTR2A and SSTR2B the transcription variants differ in their functional outcome, as exclusively SSTR2B putatively suppresses forskolin-stimulated cAMP formation [242]. Treatment of breast cancer cells with a somatostatin analog octreotide in combination with docetaxel was described as an anti-proliferative and apoptosis inducing combination [247]. In primary human somatotroph tumors SSTR2 activation by octreotide at nanomolar concentrations could induce an increased caspase-3 activity [248].…”

Section: Sstr2 As a Novel Therapeutic Targetmentioning

confidence: 99%

Molecular dissection of BV6 induced sensitization of rhabdomyosarcoma spheroids towards NK cell attack

Särchen¹

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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in early childhood. Despite recent advances in the treatment regimes of rhabdomyosarcoma, the 5-year survival is still alarmingly low for the more aggressive metastasizing alveolar rhabdomyosarcoma subtype. Novel treatment strategies are needed in order to increase the overall survival rate. Hallmarks of cancer include evade cell death induction and evade immune system surveillance. This is mediated in part by up-regulation of inhibitor of apoptosis (IAP) proteins. With the development of Smac mimetic compounds mimicking the endogenous IAP antagonist Smac, this tumor evasion mechanism became exploitable. In this PhD thesis, a combinatory approach for a putative treatment option of RMS will be presented. Here, the Smac mimetic compound BV6 will be used as a pre-treatment of RMS cells. This leads to a sensitizing effect within the tumor cells, increasing the killing efficacy of natural killer (NK) cells. Subtoxic concentrations of BV6 were chosen to sensitize RMS cells. To remodel the solid tumor characteristics of RMS, a multicellular RMS tumor spheroid culture model was used. In both tumor spheroids and conventional monolayer cell culture BV6 induced the degradation of IAP proteins (cIAP1, cIAP2, in spheroids XIAP). Further, BV6 led to the activation of both, the canonical and non-canonical NF-κB signaling pathways. This was demonstrated by an increased IκBα and p65 phosphorylation, and nuclear translocation of p-p65, indicative for an active canonical NF-κB signaling. On the other side, cIAP degradation led to the stabilization and accumulation of NIK and downstream partial degradation of p100 to p52 and its nuclear translocation, indicating non-canonical NF-κB signaling pathway activity. A bulk RNA sequencing approach of BV6 treated RH30 cells validated the NF-κB signaling involvement and identified 182 differentially expressed genes. Among the interesting target genes are NFKBIA (IκBα),BIRC3 (cIAP2), NFKB2 (p100), CCL5 and SSTR2. SSTR2 was thoroughly validated as being up-regulated on a transcriptional and on protein level. Here, SSTR2A, one of the two alternative splicing variants, is up-regulated and opens a hypothetical targeted treatment strategy, as SSTR2 expression is not associated with RMS, but rather described with neuroendocrine tumor entities. In addition, CCL5 was thoroughly validated as a BV6 induced target. Again, the up-regulated mRNA transcription was validated by an increased translation and by increased secretion of CCL5. As CCL5 being associated as pro-migratory and activating of NK cells, CRISPR/Cas9 mediated CCL5 knock-out studies were performed to evaluate the influence of CCL5 within a BV6 pre-treatment and NK cell co-cultivation setting. It was shown that CCL5 knock-out does not rescue BV6 pre-treated RMS spheroids from NK cell attack and killing. The previous mentioned transcriptional activity by BV6 stimulation was NIK mediated as knock-down of NIK reduced the mRNA transcription of several interesting genes. However, NIK mediated down-stream signaling had no influence on the BV6 induced sensitizing effect towards NK cell mediated attack. A NIK knock-down had no rescue effect upon BV6 pre-treatment and NK cell co-treatment. As cIAP proteins are present in receptor bound complexes, e.g. complex I at the TNF receptor 1 (TNFR1), a putative involvement of death receptors in general was evaluated. Indeed, BV6 treatment of RMS cells could increase the surface presentation of DR5, a death receptor ligating TRAIL. Functionally, co-treatment of BV6 with TRAIL led to an additive cell death inducting effect. However, within the NK cell co-cultivation setting, addition of a neutralizing TRAIL anitbody could not rescue BV6 pre-treated RMS spheroids from NK cell killing. A similar effect was observed when neutralizing TNFα by adding Enbrel during the NK cell co-cultivation. BV6 sensitization of RMS spheroids seems to be independent of death receptors. In addition to activating NF-κB, BV6 as a Smac mimetic is supposed to be able to release caspases bound by IAP proteins. Indeed, BV6 pre-treatment of RMS spheroids and co-cultivation with NK cells could cleave and thereby activate the executioner caspase-3. Further, treatment with a pan-caspase inhibitor, zVAD.fmk, could reduce the BV6 mediated sensitizing effect towards NK cell attack in RD spheroids. Taken together, BV6 does induce a thoroughly validated NF-κB signaling pathway, leading to a NIK mediated transcriptional signature change. However, the NF-κB activation might not be responsible for the observed sensitization. Further, BV6 in combination with NK cells led to a seemingly death receptor independent, caspase dependent cell death induction of RMS spheroids. Although the mechanism remains partially con-cealed, a therapeutic benefit by combining a cell death sensitizing compound, i.e. BV6, with cytotoxic lymphocytes is evident.

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Docetaxel in combination with octreotide shows synergistic apoptotic effect by increasing SSTR2 and SSTR5 expression levels in prostate and breast cancer cell lines

Cited by 15 publications

References 26 publications

Pulmonary Carcinoid Surface Receptor Modulation Using Histone Deacetylase Inhibitors

Pulmonary Carcinoid Surface Receptor Modulation Using Histone Deacetylase Inhibitors

Octreotide Attenuates Acute Kidney Injury after Hepatic Ischemia and Reperfusion by Enhancing Autophagy

Molecular dissection of BV6 induced sensitization of rhabdomyosarcoma spheroids towards NK cell attack

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