Pub Date : 2024-08-13DOI: 10.1021/acsptsci.4c00251
Merrill M. Froney, Christian R. Cook, Alyssa M. Cadiz, Katherine A. Flinter, Sara T. Ledeboer, Bianca Chan, Lauren E. Burris, Brian P. Hardy, Kenneth H. Pearce, Alexis C. Wardell, Brian T. Golitz, Michael B. Jarstfer, Samantha G. Pattenden
Telomeres are a protective cap that prevents chromosome ends from being recognized as double-stranded breaks. In somatic cells, telomeres shorten with each cell division due to the end replication problem, which eventually leads to senescence, a checkpoint proposed to prevent uncontrolled cell growth. Tumor cells avoid telomere shortening by activating one of two telomere maintenance mechanisms (TMMs): telomerase reactivation or alternative lengthening of telomeres (ALT). TMMs are a viable target for cancer treatment as they are not active in normal, differentiated cells. Whereas there is a telomerase inhibitor currently undergoing clinical trials, there are no known ALT inhibitors in development, partially because the complex ALT pathway is still poorly understood. For cancers such as neuroblastoma and osteosarcoma, the ALT-positive status is associated with an aggressive phenotype and few therapeutic options. Thus, methods that characterize the key biological pathways driving ALT will provide important mechanistic insight. We have developed a first-in-class phenotypic high-throughput screen to identify small-molecule inhibitors of ALT. Our screen measures relative C-circle level, an ALT-specific biomarker, to detect changes in ALT activity induced by compound treatment. To investigate epigenetic mechanisms that contribute to ALT, we screened osteosarcoma and neuroblastoma cells against an epigenetic-targeted compound library. Hits included compounds that target chromatin-regulating proteins and DNA damage repair pathways. Overall, the high-throughput C-circle assay will help expand the repertoire of potential ALT-specific therapeutic targets and increase our understanding of ALT biology.
端粒是防止染色体末端被识别为双链断裂的保护帽。在体细胞中，由于末端复制问题，端粒会随着每次细胞分裂而缩短，最终导致衰老，而衰老是为防止细胞失控生长而提出的检查点。肿瘤细胞通过激活两种端粒维持机制（TMM）之一来避免端粒缩短：端粒酶再激活或端粒替代性延长（ALT）。端粒维持机制在正常的分化细胞中并不活跃，因此是治疗癌症的可行靶点。目前有一种端粒酶抑制剂正在进行临床试验，但还没有已知的 ALT 抑制剂正在研发中，部分原因是人们对复杂的 ALT 途径还知之甚少。对于神经母细胞瘤和骨肉瘤等癌症来说，ALT 阳性与侵袭性表型和治疗选择少有关。因此，表征驱动 ALT 的关键生物通路的方法将提供重要的机理启示。我们已开发出一种首创的表型高通量筛选方法，用于鉴定 ALT 的小分子抑制剂。我们的筛选通过测量 ALT 特异性生物标志物相对 C-circle 水平来检测化合物治疗诱导的 ALT 活性变化。为了研究导致 ALT 的表观遗传机制，我们针对表观遗传靶向化合物库筛选了骨肉瘤和神经母细胞瘤细胞。命中的化合物包括靶向染色质调节蛋白和DNA损伤修复途径的化合物。总之，高通量 C-circle 检测将有助于扩大潜在 ALT 特异性治疗靶点的范围，并增加我们对 ALT 生物学的了解。
{"title":"A First-in-Class High-Throughput Screen to Discover Modulators of the Alternative Lengthening of Telomeres (ALT) Pathway","authors":"Merrill M. Froney, Christian R. Cook, Alyssa M. Cadiz, Katherine A. Flinter, Sara T. Ledeboer, Bianca Chan, Lauren E. Burris, Brian P. Hardy, Kenneth H. Pearce, Alexis C. Wardell, Brian T. Golitz, Michael B. Jarstfer, Samantha G. Pattenden","doi":"10.1021/acsptsci.4c00251","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00251","url":null,"abstract":"Telomeres are a protective cap that prevents chromosome ends from being recognized as double-stranded breaks. In somatic cells, telomeres shorten with each cell division due to the end replication problem, which eventually leads to senescence, a checkpoint proposed to prevent uncontrolled cell growth. Tumor cells avoid telomere shortening by activating one of two telomere maintenance mechanisms (TMMs): telomerase reactivation or alternative lengthening of telomeres (ALT). TMMs are a viable target for cancer treatment as they are not active in normal, differentiated cells. Whereas there is a telomerase inhibitor currently undergoing clinical trials, there are no known ALT inhibitors in development, partially because the complex ALT pathway is still poorly understood. For cancers such as neuroblastoma and osteosarcoma, the ALT-positive status is associated with an aggressive phenotype and few therapeutic options. Thus, methods that characterize the key biological pathways driving ALT will provide important mechanistic insight. We have developed a first-in-class phenotypic high-throughput screen to identify small-molecule inhibitors of ALT. Our screen measures relative C-circle level, an ALT-specific biomarker, to detect changes in ALT activity induced by compound treatment. To investigate epigenetic mechanisms that contribute to ALT, we screened osteosarcoma and neuroblastoma cells against an epigenetic-targeted compound library. Hits included compounds that target chromatin-regulating proteins and DNA damage repair pathways. Overall, the high-throughput C-circle assay will help expand the repertoire of potential ALT-specific therapeutic targets and increase our understanding of ALT biology.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142218057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-13DOI: 10.1021/acsptsci.4c00055
Rashmi J. Hemani, Priyal M. Chauhan, Ratika Srivastava, Nitiraj B. Shete, Amit S. Jojera, Shailesh M. Soni, Sishir D. Gang, Abhijit M. Konnur, Umapati N. Hegde, Hardik B. Patel, Banibrata N. Mukhopadhyay, Manan A. Raval, Sachchida Nand Pandey
Tacrolimus (TAC) has a narrow therapeutic index and shows interindividual variabilities in its blood concentration. Although guidelines recommend a genetic variant (rs776746) to determine the optimized TAC dose, discrepancies in accuracy have been noted. Therefore, studying other variants of CYP3A5 may improve the accuracy of the TAC dose. Clinical exome sequencing (CES) was performed in 219 renal transplant patients. The SNPs of CYP3A5 covered by CES were recorded. The TAC blood trough concentration/dose (C0/D) was calculated on day 7 and months 1, 3, 6, and 12 of post-transplantation, and association with CYP3A5 genotypes was studied. Further, biopsy-proven rejection and pathological events were analyzed for their association with CYP3A5 genotypes. Out of 35 variants of CYP3A5 covered in CES, rs776746, rs15524, rs4646449, and rs464645 were significantly associated with the TAC C0/D on day 7 and months 1, 3, and 6. Further analysis showed that the slow-metabolizing genotypes of all four SNPs synergistically associated with the TAC C0/D on day 7 and months 1, 3, 6, and 12. The “CC” genotype of rs776746 showed a significant association (RR = 1.613; p = 0.035) with allograft rejection. In addition, cox regression analysis showed that the presence of the “CA” genotype of rs4646453 increased (HR = 7.258; 95% CI = 1.354–38.904) the risk of development of pathological events, respectively. Four variants of CYP3A5 were synergistically associated with the TAC dose determination. In addition, rs776746 and rs4646453 may be associated with allograft rejection and pathological events, respectively.
{"title":"Synergistic Effect of Cytochrome P450 Family 3 Subfamily A Member 5 (CYP3A5) Genetic Variants in Tacrolimus Dose Determination in Indian Renal Transplant Patients","authors":"Rashmi J. Hemani, Priyal M. Chauhan, Ratika Srivastava, Nitiraj B. Shete, Amit S. Jojera, Shailesh M. Soni, Sishir D. Gang, Abhijit M. Konnur, Umapati N. Hegde, Hardik B. Patel, Banibrata N. Mukhopadhyay, Manan A. Raval, Sachchida Nand Pandey","doi":"10.1021/acsptsci.4c00055","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00055","url":null,"abstract":"Tacrolimus (TAC) has a narrow therapeutic index and shows interindividual variabilities in its blood concentration. Although guidelines recommend a genetic variant (rs776746) to determine the optimized TAC dose, discrepancies in accuracy have been noted. Therefore, studying other variants of <i>CYP3A5</i> may improve the accuracy of the TAC dose. Clinical exome sequencing (CES) was performed in 219 renal transplant patients. The SNPs of <i>CYP3A5</i> covered by CES were recorded. The TAC blood trough concentration/dose (<i>C</i><sub>0</sub>/<i>D</i>) was calculated on day 7 and months 1, 3, 6, and 12 of post-transplantation, and association with <i>CYP3A5</i> genotypes was studied. Further, biopsy-proven rejection and pathological events were analyzed for their association with <i>CYP3A5</i> genotypes. Out of 35 variants of <i>CYP3A5</i> covered in CES, rs776746, rs15524, rs4646449, and rs464645 were significantly associated with the TAC <i>C</i><sub>0</sub>/<i>D</i> on day 7 and months 1, 3, and 6. Further analysis showed that the slow-metabolizing genotypes of all four SNPs synergistically associated with the TAC <i>C</i><sub>0</sub>/<i>D</i> on day 7 and months 1, 3, 6, and 12. The “CC” genotype of rs776746 showed a significant association (RR = 1.613; <i>p</i> = 0.035) with allograft rejection. In addition, cox regression analysis showed that the presence of the “CA” genotype of rs4646453 increased (HR = 7.258; 95% CI = 1.354–38.904) the risk of development of pathological events, respectively. Four variants of <i>CYP3A5</i> were synergistically associated with the TAC dose determination. In addition, rs776746 and rs4646453 may be associated with allograft rejection and pathological events, respectively.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142218058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The role of autotaxin (ATX)-lysophosphatidic acid (LPA) is yet to be explored in the context of liver cirrhosis and associated encephalopathy. Our objective of this study was to evaluate the role of an ATX inhibitor in biliary cirrhosis and associated hepatic encephalopathy in rats. The preliminary investigation revealed significant impairment in liver function, which eventually led to the development of hepatic encephalopathy. Interestingly, LPA levels were significantly increased in the plasma, liver, and brain of rats following bile duct ligation. Subsequently, we tested the efficacy of an ATX inhibitor, CBT-295, in bile duct-induced biliary cirrhosis and neuropsychiatric symptoms associated with hepatic encephalopathy. CBT-295 showed good oral bioavailability and favorable pharmacokinetic properties. CBT-295 exhibited a significant reduction in inflammatory cytokines like TGF-β, TNF-α, and IL-6 levels, also reduced bile duct proliferation marker CK-19, and lowered liver fibrosis, as evident from reduced collagen deposition. The reversal of liver fibrosis with CBT-295 led to a reduction in blood and brain ammonia levels. Furthermore, CBT-295 also reduced neuroinflammation induced by ammonia, which is characterized by a significant reduction in brain cytokine levels. It improved neuropsychiatric symptoms such as locomotor activities, cognitive impairment, and clinical grading scores associated with hepatic encephalopathy. The improvement in hepatic encephalopathy observed with the ATX inhibitor could be the result of its hepatoprotective action and its ability to attenuate neuroinflammation. Therefore, inhibition of ATX-LPA signaling can be a multifactorial approach for the treatment of chronic liver diseases.
{"title":"Effect of an Autotaxin Inhibitor, 2-(4-Chlorophenyl)-7-methyl-8-pentylimidazo[1,2-a] Pyrimidin-5(8H)-one (CBT-295), on Bile Duct Ligation-Induced Chronic Liver Disease and Associated Hepatic Encephalopathy in Rats","authors":"Subhasis Roy, Monali Chakrabarti, Trisha Mondal, Tapas Kumar Das, Tonmoy Sarkar, Sebak Datta, Mrinalkanti Kundu, Manish Banerjee, Onkar Prakash Kulkarni","doi":"10.1021/acsptsci.4c00066","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00066","url":null,"abstract":"The role of autotaxin (ATX)-lysophosphatidic acid (LPA) is yet to be explored in the context of liver cirrhosis and associated encephalopathy. Our objective of this study was to evaluate the role of an ATX inhibitor in biliary cirrhosis and associated hepatic encephalopathy in rats. The preliminary investigation revealed significant impairment in liver function, which eventually led to the development of hepatic encephalopathy. Interestingly, LPA levels were significantly increased in the plasma, liver, and brain of rats following bile duct ligation. Subsequently, we tested the efficacy of an ATX inhibitor, CBT-295, in bile duct-induced biliary cirrhosis and neuropsychiatric symptoms associated with hepatic encephalopathy. CBT-295 showed good oral bioavailability and favorable pharmacokinetic properties. CBT-295 exhibited a significant reduction in inflammatory cytokines like TGF-β, TNF-α, and IL-6 levels, also reduced bile duct proliferation marker CK-19, and lowered liver fibrosis, as evident from reduced collagen deposition. The reversal of liver fibrosis with CBT-295 led to a reduction in blood and brain ammonia levels. Furthermore, CBT-295 also reduced neuroinflammation induced by ammonia, which is characterized by a significant reduction in brain cytokine levels. It improved neuropsychiatric symptoms such as locomotor activities, cognitive impairment, and clinical grading scores associated with hepatic encephalopathy. The improvement in hepatic encephalopathy observed with the ATX inhibitor could be the result of its hepatoprotective action and its ability to attenuate neuroinflammation. Therefore, inhibition of ATX-LPA signaling can be a multifactorial approach for the treatment of chronic liver diseases.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142218059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-12DOI: 10.1021/acsptsci.4c00301
Subham Guin, Akash Ashokan, Alan Pollack, Shanta Dhar
Mainstream treatment modalities which dominate the therapeutic landscape of prostate cancer (PCa) are prostatectomy, radiation therapy, and androgen deprivation therapy (ADT) or castration. These therapeutic options can extend the life expectancy of the patients but eventually fail to completely cure the disease. Despite undergoing ADT, patients still experience disease recurrence. One of the reasons for this recurrence is the binding of the basal androgens present in blood plasma to the androgen receptor (AR). At this stage, the disease becomes castration-resistant prostate cancer (CRPC) showing resistance to ADT promoting progression, and there is no effective treatment available. Although another male cancer such as testicular cancer responds to cisplatin-based therapy very well, PCa is resistant to cisplatin. In our continued effort to find the pathways that are important for such resistance, we link in this report, tumor metabolism driven androgen regulation and PCa resistance toward cisplatin-based therapy. To delve deeper into understanding how metabolic modulatory cisplatin prodrugs can be used to target the ADT resistant population, we demonstrate that metabolic inhibition by a cisplatin prodrug, Platin-L has the potential to modulate AR activity and resensitize ADT resistant cells toward cisplatin-based chemotherapy as well as ADT. The mode of action for Platin-L is inhibition of fatty acid oxidation (FAO) of prostate cancer cells. We demonstrated that FAO inhibition by Platin-L in PCa cells contribute to AR regulation resulting in altered tumorigenicity of androgen sensitive prostate cancer.
{"title":"Lipid Metabolism Modulatory Cisplatin Prodrug Sensitizes Resistant Prostate Cancer toward Androgen Deprivation Therapy","authors":"Subham Guin, Akash Ashokan, Alan Pollack, Shanta Dhar","doi":"10.1021/acsptsci.4c00301","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00301","url":null,"abstract":"Mainstream treatment modalities which dominate the therapeutic landscape of prostate cancer (PCa) are prostatectomy, radiation therapy, and androgen deprivation therapy (ADT) or castration. These therapeutic options can extend the life expectancy of the patients but eventually fail to completely cure the disease. Despite undergoing ADT, patients still experience disease recurrence. One of the reasons for this recurrence is the binding of the basal androgens present in blood plasma to the androgen receptor (AR). At this stage, the disease becomes castration-resistant prostate cancer (CRPC) showing resistance to ADT promoting progression, and there is no effective treatment available. Although another male cancer such as testicular cancer responds to cisplatin-based therapy very well, PCa is resistant to cisplatin. In our continued effort to find the pathways that are important for such resistance, we link in this report, tumor metabolism driven androgen regulation and PCa resistance toward cisplatin-based therapy. To delve deeper into understanding how metabolic modulatory cisplatin prodrugs can be used to target the ADT resistant population, we demonstrate that metabolic inhibition by a cisplatin prodrug, Platin-L has the potential to modulate AR activity and resensitize ADT resistant cells toward cisplatin-based chemotherapy as well as ADT. The mode of action for Platin-L is inhibition of fatty acid oxidation (FAO) of prostate cancer cells. We demonstrated that FAO inhibition by Platin-L in PCa cells contribute to AR regulation resulting in altered tumorigenicity of androgen sensitive prostate cancer.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"131 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141934064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-12DOI: 10.1021/acsptsci.4c00190
Patrik Oleksak, David Rysanek, Marketa Vancurova, Pavla Vasicova, Alexandra Urbancokova, Josef Novak, Dominika Maurencova, Pavel Kashmel, Jana Houserova, Romana Mikyskova, Ondrej Novotny, Milan Reinis, Pavel Juda, Miroslav Hons, Jirina Kroupova, David Sedlak, Tetyana Sulimenko, Pavel Draber, Marketa Chlubnova, Eugenie Nepovimova, Kamil Kuca, Miroslav Lisa, Rudolf Andrys, Tereza Kobrlova, Ondrej Soukup, Jiri Janousek, Lukas Prchal, Jiri Bartek, Kamil Musilek, Zdenek Hodny
6-Nitrobenzo[b]thiophene 1,1-dioxide (Stattic) is a potent signal transducer and activator of the transcription 3 (STAT3) inhibitor developed originally for anticancer therapy. However, Stattic harbors several STAT3 inhibition-independent biological effects. To improve the properties of Stattic, we prepared a series of analogues derived from 6-aminobenzo[b]thiophene 1,1-dioxide, a compound directly obtained from the reduction of Stattic, that includes a methoxybenzylamino derivative (K2071) with optimized physicochemical characteristics, including the ability to cross the blood–brain barrier. Besides inhibiting the interleukin-6-stimulated activity of STAT3 mediated by tyrosine 705 phosphorylation, K2071 also showed cytotoxicity against a set of human glioblastoma-derived cell lines. In contrast to the core compound, a part of K2071 cytotoxicity reflected a STAT3 inhibition-independent block of mitotic progression in the prophase, affecting mitotic spindle formation, indicating that K2071 also acts as a mitotic poison. Compared to Stattic, K2071 was significantly less thiol-reactive. In addition, K2071 affected cell migration, suppressed cell proliferation in tumor spheroids, exerted cytotoxicity for glioblastoma temozolomide-induced senescent cells, and inhibited the secretion of the proinflammatory cytokine monocyte chemoattractant protein 1 (MCP-1) in senescent cells. Importantly, K2071 was well tolerated in mice, lacking manifestations of acute toxicity. The structure–activity relationship analysis of the K2071 molecule revealed the necessity of the para-substituted methoxyphenyl motif for antimitotic but not overall cytotoxic activity of its derivatives. Altogether, these results indicate that compound K2071 is a novel Stattic-derived STAT3 inhibitor and a mitotic poison with anticancer and senotherapeutic properties that is effective on glioblastoma cells and may be further developed as an agent for glioblastoma therapy.
{"title":"Discovery of a 6-Aminobenzo[b]thiophene 1,1-Dioxide Derivative (K2071) with a Signal Transducer and Activator of Transcription 3 Inhibitory, Antimitotic, and Senotherapeutic Activities","authors":"Patrik Oleksak, David Rysanek, Marketa Vancurova, Pavla Vasicova, Alexandra Urbancokova, Josef Novak, Dominika Maurencova, Pavel Kashmel, Jana Houserova, Romana Mikyskova, Ondrej Novotny, Milan Reinis, Pavel Juda, Miroslav Hons, Jirina Kroupova, David Sedlak, Tetyana Sulimenko, Pavel Draber, Marketa Chlubnova, Eugenie Nepovimova, Kamil Kuca, Miroslav Lisa, Rudolf Andrys, Tereza Kobrlova, Ondrej Soukup, Jiri Janousek, Lukas Prchal, Jiri Bartek, Kamil Musilek, Zdenek Hodny","doi":"10.1021/acsptsci.4c00190","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00190","url":null,"abstract":"6-Nitrobenzo[<i>b</i>]thiophene 1,1-dioxide (Stattic) is a potent signal transducer and activator of the transcription 3 (STAT3) inhibitor developed originally for anticancer therapy. However, Stattic harbors several STAT3 inhibition-independent biological effects. To improve the properties of Stattic, we prepared a series of analogues derived from 6-aminobenzo[<i>b</i>]thiophene 1,1-dioxide, a compound directly obtained from the reduction of Stattic, that includes a methoxybenzylamino derivative (K2071) with optimized physicochemical characteristics, including the ability to cross the blood–brain barrier. Besides inhibiting the interleukin-6-stimulated activity of STAT3 mediated by tyrosine 705 phosphorylation, K2071 also showed cytotoxicity against a set of human glioblastoma-derived cell lines. In contrast to the core compound, a part of K2071 cytotoxicity reflected a STAT3 inhibition-independent block of mitotic progression in the prophase, affecting mitotic spindle formation, indicating that K2071 also acts as a mitotic poison. Compared to Stattic, K2071 was significantly less thiol-reactive. In addition, K2071 affected cell migration, suppressed cell proliferation in tumor spheroids, exerted cytotoxicity for glioblastoma temozolomide-induced senescent cells, and inhibited the secretion of the proinflammatory cytokine monocyte chemoattractant protein 1 (MCP-1) in senescent cells. Importantly, K2071 was well tolerated in mice, lacking manifestations of acute toxicity. The structure–activity relationship analysis of the K2071 molecule revealed the necessity of the <i>para</i>-substituted methoxyphenyl motif for antimitotic but not overall cytotoxic activity of its derivatives. Altogether, these results indicate that compound K2071 is a novel Stattic-derived STAT3 inhibitor and a mitotic poison with anticancer and senotherapeutic properties that is effective on glioblastoma cells and may be further developed as an agent for glioblastoma therapy.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"58 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142218183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Synthetic DNAzyme-based structures enable dynamic cell regulation. However, engineering an effective and targeted DNAzyme-based structure to perform customizable multistep regulation remains largely unexplored. Herein, we designed a membrane-anchored DNAzyme-based molecular machine to implement dynamic inter- and intracellular cascade regulation, which realizes efficient T-cell/cancer cell interactions and subsequent receptor mediated cancer cell uptake. Using CD8+ T-cells and HeLa cancer cells as a proof of concept, we demonstrate that the designed DNAzyme-based molecular machine enables customized cascade regulation including (1) specific recognition between T-cells and cancer cells, (2) specific response and fluorescence sensing upon extracellular stimuli, and (3) cascade regulation including intercellular distance shortening, cell–cell communication, and intracellular delivery of anticancer drugs. Together, this work provides a promising pathway for customized cascade cell regulation based on a DNAzyme-based molecular machine, which enables enhanced cancer therapy by combining T-cell immunotherapy and chemotherapy.
基于 DNA 酶的合成结构可实现动态细胞调控。然而，如何设计出一种有效且有针对性的 DNA 酶基结构，以实现可定制的多步骤调控，目前仍有许多研究尚未完成。在此，我们设计了一种基于膜锚定 DNA 酶的分子机器，以实现细胞间和细胞内的动态级联调控，从而实现高效的 T 细胞/癌细胞相互作用以及随后受体介导的癌细胞摄取。我们利用 CD8+ T 细胞和 HeLa 癌细胞作为概念验证，证明所设计的基于 DNA 酶的分子机器可实现定制级联调节，包括：（1）T 细胞和癌细胞之间的特异性识别；（2）对细胞外刺激的特异性响应和荧光感应；以及（3）包括细胞间距离缩短、细胞间通信和抗癌药物细胞内递送在内的级联调节。总之，这项研究工作为基于 DNA 酶的分子机器的定制级联细胞调控提供了一条前景广阔的途径，从而能够通过结合 T 细胞免疫疗法和化疗来加强癌症治疗。
{"title":"Design of a Membrane-Anchored DNAzyme-Based Molecular Machine for Enhanced Cancer Therapy by Customized Cascade Regulation","authors":"Man-Sha Wu, Ze-Rui Zhou, Xiao-Yuan Wang, Xi-Chen Du, Da-Wei Li, Ruo-Can Qian","doi":"10.1021/acsptsci.4c00362","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00362","url":null,"abstract":"Synthetic DNAzyme-based structures enable dynamic cell regulation. However, engineering an effective and targeted DNAzyme-based structure to perform customizable multistep regulation remains largely unexplored. Herein, we designed a membrane-anchored DNAzyme-based molecular machine to implement dynamic inter- and intracellular cascade regulation, which realizes efficient T-cell/cancer cell interactions and subsequent receptor mediated cancer cell uptake. Using CD8<sup>+</sup> T-cells and HeLa cancer cells as a proof of concept, we demonstrate that the designed DNAzyme-based molecular machine enables customized cascade regulation including (1) specific recognition between T-cells and cancer cells, (2) specific response and fluorescence sensing upon extracellular stimuli, and (3) cascade regulation including intercellular distance shortening, cell–cell communication, and intracellular delivery of anticancer drugs. Together, this work provides a promising pathway for customized cascade cell regulation based on a DNAzyme-based molecular machine, which enables enhanced cancer therapy by combining T-cell immunotherapy and chemotherapy.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141934158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-06DOI: 10.1021/acsptsci.3c00394
Moein Ala
Pancreatic ductal adenocarcinoma (PDAC) is the seventh most common cause of cancer-related mortality. Despite different methods of treatment, nearly more than 90% of patients with PDAC die shortly after diagnosis. Contrary to promising results in other cancers, immune checkpoint inhibitors (ICIs) showed limited success in PDAC. Recent studies have shown that noncoding RNAs (ncRNAs) are extensively involved in PDAC cell–immune cell interaction and mediate immune evasion in this vicious cancer. PDAC cells recruit numerous ncRNAs to widely affect the phenotype and function of immune cells through various mechanisms. For instance, PDAC cells upregulate miR-301a and downregulate miR-340 to induce M2 polarization of macrophages or overexpress miR-203, miR-146a, and miR-212-3p to downregulate toll-like receptor 4 (TLR4), CD80, CD86, CD1a, major histocompatibility complex (MHC) II, and CD83, thereby evading recognition by dendritic cells. By downregulating miR-4299 and miR-153, PDAC cells can decrease the expression of NK group 2D (NKG2D) and MHC class I chain-related molecules A and B (MICA/B) to blunt the natural killer (NK) cell response. PDAC cells also highly express lncRNA AL137789.1, hsa_circ_0046523, lncRNA LINC00460, and miR-155-5p to upregulate immune checkpoint proteins and escape T cell cytotoxicity. On the other hand, ncRNAs derived from suppressive immune cells promote proliferation, invasion, and drug resistance in PDAC cells. ncRNAs can be applied to overcome resistance to ICIs, monitor the immune microenvironment of PDAC, and predict response to ICIs. This Review article comprehensively discusses recent findings regarding the roles of ncRNAs in the immune evasion of PDAC.
{"title":"Noncoding Ribonucleic Acids (RNAs) May Improve Response to Immunotherapy in Pancreatic Cancer","authors":"Moein Ala","doi":"10.1021/acsptsci.3c00394","DOIUrl":"https://doi.org/10.1021/acsptsci.3c00394","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is the seventh most common cause of cancer-related mortality. Despite different methods of treatment, nearly more than 90% of patients with PDAC die shortly after diagnosis. Contrary to promising results in other cancers, immune checkpoint inhibitors (ICIs) showed limited success in PDAC. Recent studies have shown that noncoding RNAs (ncRNAs) are extensively involved in PDAC cell–immune cell interaction and mediate immune evasion in this vicious cancer. PDAC cells recruit numerous ncRNAs to widely affect the phenotype and function of immune cells through various mechanisms. For instance, PDAC cells upregulate miR-301a and downregulate miR-340 to induce M2 polarization of macrophages or overexpress miR-203, miR-146a, and miR-212-3p to downregulate toll-like receptor 4 (TLR4), CD80, CD86, CD1a, major histocompatibility complex (MHC) II, and CD83, thereby evading recognition by dendritic cells. By downregulating miR-4299 and miR-153, PDAC cells can decrease the expression of NK group 2D (NKG2D) and MHC class I chain-related molecules A and B (MICA/B) to blunt the natural killer (NK) cell response. PDAC cells also highly express lncRNA AL137789.1, hsa_circ_0046523, lncRNA LINC00460, and miR-155-5p to upregulate immune checkpoint proteins and escape T cell cytotoxicity. On the other hand, ncRNAs derived from suppressive immune cells promote proliferation, invasion, and drug resistance in PDAC cells. ncRNAs can be applied to overcome resistance to ICIs, monitor the immune microenvironment of PDAC, and predict response to ICIs. This Review article comprehensively discusses recent findings regarding the roles of ncRNAs in the immune evasion of PDAC.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141934066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-06DOI: 10.1021/acsptsci.4c00299
Núria Nadal-Gratacós, Martalu D. Pazos, David Pubill, Jorge Camarasa, Elena Escubedo, Xavier Berzosa, Raúl López-Arnau
The escalating prevalence of new psychoactive substances (NPSs) poses a significant public health challenge, evidenced by the vast chemical diversity, with over 500 substances reported annually to the United Nations Office on Drugs and Crime-Early Warning Advisory (UNODC-EWA) in the past five years. Among NPSs, synthetic cathinones are gaining a lot of popularity among users. Notably, synthetic cathinones accounted for approximately 50% of the total quantity of NPSs reported as seized by EU Member States in 2021. Preliminary data from UNODC indicates that a total of 209 synthetic cathinones have been reported to date. As their popularity grows, studying the structure–activity relationship (SAR) of synthetic cathinones is essential. SAR studies elucidate how structural features impact biological effects, aiding in toxicity prediction, regulatory compliance, and forensic identification. Additionally, SAR studies play a pivotal role in guiding drug policies, aiding authorities in categorizing and regulating newly emerging synthetic cathinones, mitigate public health risks and offer valuable insights into potential therapeutic applications. Thus, our Review consolidates recent findings on the effects of different substitutions in the chemical scaffold of synthetic cathinones on their mechanism of action as well as pharmacological and toxicological effects of synthetic cathinones, thus enhancing understanding of the SAR of synthetic cathinones’ pharmacology and potential implications.
{"title":"Structure–Activity Relationship of Synthetic Cathinones: An Updated Review","authors":"Núria Nadal-Gratacós, Martalu D. Pazos, David Pubill, Jorge Camarasa, Elena Escubedo, Xavier Berzosa, Raúl López-Arnau","doi":"10.1021/acsptsci.4c00299","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00299","url":null,"abstract":"The escalating prevalence of new psychoactive substances (NPSs) poses a significant public health challenge, evidenced by the vast chemical diversity, with over 500 substances reported annually to the United Nations Office on Drugs and Crime-Early Warning Advisory (UNODC-EWA) in the past five years. Among NPSs, synthetic cathinones are gaining a lot of popularity among users. Notably, synthetic cathinones accounted for approximately 50% of the total quantity of NPSs reported as seized by EU Member States in 2021. Preliminary data from UNODC indicates that a total of 209 synthetic cathinones have been reported to date. As their popularity grows, studying the structure–activity relationship (SAR) of synthetic cathinones is essential. SAR studies elucidate how structural features impact biological effects, aiding in toxicity prediction, regulatory compliance, and forensic identification. Additionally, SAR studies play a pivotal role in guiding drug policies, aiding authorities in categorizing and regulating newly emerging synthetic cathinones, mitigate public health risks and offer valuable insights into potential therapeutic applications. Thus, our Review consolidates recent findings on the effects of different substitutions in the chemical scaffold of synthetic cathinones on their mechanism of action as well as pharmacological and toxicological effects of synthetic cathinones, thus enhancing understanding of the SAR of synthetic cathinones’ pharmacology and potential implications.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"77 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141934065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The potential for multiorgan toxicities is a significant barrier to the therapeutic use of doxorubicin (DOX) in cancer treatment. With regard to DOX-induced acute cardiotoxicity in rats, the current investigation sought to assess the cardioprotective function of α-bisabolol (BSB) as well as the underlying pharmacological and molecular processes. Acute cardiotoxicity was induced in the rats by the intraperitoneal injection of DOX (12.5 mg/kg, single dosage). Over the course of 5 days, the rats were administered 25 mg/kg of BSB orally twice a day. The DOX administration induced cardiac damage, as evidenced by altered cardiospecific diagnostic markers and macroscopic enzyme mapping assay. The occurrence of mitochondrial oxidative stress was observed by a significant decline in antioxidant defense along with an increase in lipid peroxidation. DOX also perturbed DNA damage, mitochondrial biogenesis, mitochondrial fission and dysfunction, ER stress, Hippo signaling, and caspase-dependent and independent apoptosis including necroptosis and ferroptosis in the myocardium of rats. Conversely, it has been noted that the administration of BSB preserves the myocardium and reverses all cellular, molecular, and structural disruptions in the cardiac tissues of rats exposed to DOX-induced toxicity. The results that are currently available unequivocally show the cardioprotective role of BSB in DOX-induced cardiotoxicity. This effect is attributed to BSB’s strong antioxidant, antilipid peroxidative, and antiapoptotic properties, which are mediated by advantageous changes in multiple signaling pathways.
{"title":"α-Bisabolol: A Dietary Sesquiterpene that Attenuates Apoptotic and Nonapoptotic Cell Death Pathways by Regulating the Mitochondrial Biogenesis and Endoplasmic Reticulum Stress–Hippo Signaling Axis in Doxorubicin-Induced Acute Cardiotoxicity in Rats","authors":"Nagoor Meeran MF, Seenipandi Arunachalam, Azimullah Sheikh, Dhanya Saraswathiamma, Alia Albawardi, Saeeda Al Marzooqi, Niraj Kumar Jha, Sandeep Subramanya, Rami Beiram, Shreesh Ojha","doi":"10.1021/acsptsci.4c00108","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00108","url":null,"abstract":"The potential for multiorgan toxicities is a significant barrier to the therapeutic use of doxorubicin (DOX) in cancer treatment. With regard to DOX-induced acute cardiotoxicity in rats, the current investigation sought to assess the cardioprotective function of α-bisabolol (BSB) as well as the underlying pharmacological and molecular processes. Acute cardiotoxicity was induced in the rats by the intraperitoneal injection of DOX (12.5 mg/kg, single dosage). Over the course of 5 days, the rats were administered 25 mg/kg of BSB orally twice a day. The DOX administration induced cardiac damage, as evidenced by altered cardiospecific diagnostic markers and macroscopic enzyme mapping assay. The occurrence of mitochondrial oxidative stress was observed by a significant decline in antioxidant defense along with an increase in lipid peroxidation. DOX also perturbed DNA damage, mitochondrial biogenesis, mitochondrial fission and dysfunction, ER stress, Hippo signaling, and caspase-dependent and independent apoptosis including necroptosis and ferroptosis in the myocardium of rats. Conversely, it has been noted that the administration of BSB preserves the myocardium and reverses all cellular, molecular, and structural disruptions in the cardiac tissues of rats exposed to DOX-induced toxicity. The results that are currently available unequivocally show the cardioprotective role of BSB in DOX-induced cardiotoxicity. This effect is attributed to BSB’s strong antioxidant, antilipid peroxidative, and antiapoptotic properties, which are mediated by advantageous changes in multiple signaling pathways.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"54 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141934152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-02DOI: 10.1021/acsptsci.4c00152
Hayder Ridha-Salman, Elaf Mahmood Shihab, Hasanain Kamil Hasan, Alaa Hamza Abbas, Shan Mohammed Khorsheed, Salar Ayad Fakhri
Psoriasis is a chronic, inflammatory dermatosis characterized by thickened, reddened, and scaly skin lesions. Norfloxacin is a fluoroquinolone antibiotic with enhanced antioxidant, anti-inflammatory, and immunomodulatory bioactivities. The aim of this study was to figure out the possible impact of topical norfloxacin on an imiquimod-induced model of psoriasis in mice. Thirty albino-type mice were split into five distinct groups of six animals each. The control group included healthy mice that had not received any treatment. The induction group was given the vehicle 2 h after the topical imiquimod, once daily for 8 days. Two hours after receiving topical imiquimod, the treatment groups including calcipotriol, norfloxacin 2.5%, and norfloxacin 5% were given topical ointments containing calcipotriol 0.005%, norfloxacin 2.5%, and norfloxacin 5%, for 8 days. Topical norfloxacin ointment significantly reduced the severity of imiquimod-exacerbated psoriatic lesions including erythema, shiny-white scaling, and acanthosis and fixed histological abnormalities. Furthermore, imiquimod-subjected mice treated with a higher concentration of norfloxacin ointment exhibited dramatically lower skin levels of inflammation-related biomarkers like IFN-γ, TNF-α, IL-6, IL-17A, IL-23, and TGF-β but higher levels of IL-10. They also demonstrated a notable decrease in angiogenesis parameters such as VEGF and IL-8, a substantial reduction in oxidative indicators like MDA and MPO, and a considerable rise in antioxidant enzymes like SOD and CAT. This study offers novel evidence that norfloxacin may assist in controlling inflammatory dermatoses like psoriasis by minimizing the severity of psoriatic plaques, correcting histological alterations, and diminishing the production of inflammatory, oxidative, and angiogenetic parameters.
{"title":"Mitigative Effects of Topical Norfloxacin on an Imiquimod-Induced Murine Model of Psoriasis","authors":"Hayder Ridha-Salman, Elaf Mahmood Shihab, Hasanain Kamil Hasan, Alaa Hamza Abbas, Shan Mohammed Khorsheed, Salar Ayad Fakhri","doi":"10.1021/acsptsci.4c00152","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00152","url":null,"abstract":"Psoriasis is a chronic, inflammatory dermatosis characterized by thickened, reddened, and scaly skin lesions. Norfloxacin is a fluoroquinolone antibiotic with enhanced antioxidant, anti-inflammatory, and immunomodulatory bioactivities. The aim of this study was to figure out the possible impact of topical norfloxacin on an imiquimod-induced model of psoriasis in mice. Thirty albino-type mice were split into five distinct groups of six animals each. The control group included healthy mice that had not received any treatment. The induction group was given the vehicle 2 h after the topical imiquimod, once daily for 8 days. Two hours after receiving topical imiquimod, the treatment groups including calcipotriol, norfloxacin 2.5%, and norfloxacin 5% were given topical ointments containing calcipotriol 0.005%, norfloxacin 2.5%, and norfloxacin 5%, for 8 days. Topical norfloxacin ointment significantly reduced the severity of imiquimod-exacerbated psoriatic lesions including erythema, shiny-white scaling, and acanthosis and fixed histological abnormalities. Furthermore, imiquimod-subjected mice treated with a higher concentration of norfloxacin ointment exhibited dramatically lower skin levels of inflammation-related biomarkers like IFN-γ, TNF-α, IL-6, IL-17A, IL-23, and TGF-β but higher levels of IL-10. They also demonstrated a notable decrease in angiogenesis parameters such as VEGF and IL-8, a substantial reduction in oxidative indicators like MDA and MPO, and a considerable rise in antioxidant enzymes like SOD and CAT. This study offers novel evidence that norfloxacin may assist in controlling inflammatory dermatoses like psoriasis by minimizing the severity of psoriatic plaques, correcting histological alterations, and diminishing the production of inflammatory, oxidative, and angiogenetic parameters.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141884654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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