Research

18 pages, 6492 KiB

Open AccessArticle

Heat Shock Proteins HSPA1 and HSP90AA1 Are Upregulated in Colorectal Polyps and Can Be Targeted in Cancer Cells by Anti-Inflammatory Oxicams with Arylpiperazine Pharmacophore and Benzoyl Moiety Substitutions at Thiazine Ring

by Izabela Szczuka, Jarosław Wierzbicki, Paweł Serek, Berenika M. Szczęśniak-Sięga and Małgorzata Krzystek-Korpacka

Biomolecules 2021, 11(11), 1588; https://doi.org/10.3390/biom11111588 - 27 Oct 2021

Cited by 18 | Viewed by 2406

Abstract

Heat shock proteins HSPA1/Hsp70α and HSP90AA1/Hsp90α are crucial for cancer growth but their expression pattern in colorectal polyps or whether they can be modulated by oxicams is unknown. We quantified (RTqPCR) HSPA1 and HSP90AA1 expression in 50 polyp-normal pairs in relation to polyp [...] Read more.

Heat shock proteins HSPA1/Hsp70α and HSP90AA1/Hsp90α are crucial for cancer growth but their expression pattern in colorectal polyps or whether they can be modulated by oxicams is unknown. We quantified (RTqPCR) HSPA1 and HSP90AA1 expression in 50 polyp-normal pairs in relation to polyp malignancy potential and examined the effect of piroxicam, meloxicam and five novel analogues on HSPA1 and HSP90AA1 expression (mRNA/protein) in colorectal adenocarcinoma lines. HSPA1 and HSP90AA1 were upregulated in polyps by 3- and 2.9-fold. Expression ratios were higher in polyps with higher dysplasia grade and dominant villous growth pattern, mostly a result of diminished gene expression in normal tissue. Classic oxicams had negligible/non-significant effect on HSP expression. Their most effective analogue inhibited HSPA1 protein and gene by 2.5-fold and 5.7-fold in Caco-2 and by 11.5-fold and 6.8-fold in HCT116 and HSPA1 protein in HT-29 by 1.9-fold. It downregulated HSP90AA1 protein and gene by 1.9-fold and 3.7-fold in Caco-2 and by 2-fold and 5.0-fold in HCT116. HSPA1 and HSP90AA1 are upregulated in colorectal polyps reflecting their potential for malignancy. HSPA1 in cancer cells and, to lesser degree, HSP90AA1 can be reduced by oxicam analogues with thiazine ring substituted via propylene linker by arylpiperazine pharmacophore with fluorine substituents and by benzoyl moiety. Full article

(This article belongs to the Special Issue Repurposing Drugs for Anti-Cancer Therapy)

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21 pages, 2013 KiB

Open AccessArticle

Repurposing Disulfiram for Targeting of Glioblastoma Stem Cells: An In Vitro Study

by Lisa Zirjacks, Nicolai Stransky, Lukas Klumpp, Lukas Prause, Franziska Eckert, Daniel Zips, Sabine Schleicher, Rupert Handgretinger, Stephan M. Huber and Katrin Ganser

Biomolecules 2021, 11(11), 1561; https://doi.org/10.3390/biom11111561 - 21 Oct 2021

Cited by 8 | Viewed by 2382

Abstract

Mesenchymal glioblastoma stem cells (GSCs), a subpopulation in glioblastoma that are responsible for therapy resistance and tumor spreading in the brain, reportedly upregulate aldehyde dehydrogenase isoform-1A3 (ALDH1A3) which can be inhibited by disulfiram (DSF), an FDA-approved drug formerly prescribed in alcohol use disorder. [...] Read more.

Mesenchymal glioblastoma stem cells (GSCs), a subpopulation in glioblastoma that are responsible for therapy resistance and tumor spreading in the brain, reportedly upregulate aldehyde dehydrogenase isoform-1A3 (ALDH1A3) which can be inhibited by disulfiram (DSF), an FDA-approved drug formerly prescribed in alcohol use disorder. Reportedly, DSF in combination with Cu²⁺ ions exerts multiple tumoricidal, chemo- and radio-therapy-sensitizing effects in several tumor entities. The present study aimed to quantify these DSF effects in glioblastoma stem cells in vitro, regarding dependence on ALDH1A3 expression. To this end, two patient-derived GSC cultures with differing ALDH1A3 expression were pretreated (in the presence of CuSO₄, 100 nM) with DSF (0 or 100 nM) and the DNA-alkylating agent temozolomide (0 or 30 µM) and then cells were irradiated with a single dose of 0–8 Gy. As read-outs, cell cycle distribution and clonogenic survival were determined by flow cytometry and limited dilution assay, respectively. As a result, DSF modulated cell cycle distribution in both GSC cultures and dramatically decreased clonogenic survival independently of ALDH1A3 expression. This effect was additive to the impairment of clonogenic survival by radiation, but not associated with radiosensitization. Of note, cotreatment with temozolomide blunted the DSF inhibition of clonogenic survival. In conclusion, DSF targets GSCs independent of ALDH1A3 expression, suggesting a therapeutic efficacy also in glioblastomas with low mesenchymal GSC populations. As temozolomide somehow antagonized the DSF effects, strategies for future combination of DSF with the adjuvant standard therapy (fractionated radiotherapy and concomitant temozolomide chemotherapy followed by temozolomide maintenance therapy) are not supported by the present study. Full article

(This article belongs to the Special Issue Repurposing Drugs for Anti-Cancer Therapy)

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14 pages, 3202 KiB

Open AccessArticle

Dual Blockade of Lactate/GPR81 and PD-1/PD-L1 Pathways Enhances the Anti-Tumor Effects of Metformin

by Shaomeng Chen, Xiuman Zhou, Xin Yang, Wanqiong Li, Shuzhen Li, Zheng Hu, Chen Ling, Ranran Shi, Juan Liu, Guanyu Chen, Nazi Song, Xianxing Jiang, Xinghua Sui and Yanfeng Gao

Biomolecules 2021, 11(9), 1373; https://doi.org/10.3390/biom11091373 - 17 Sep 2021

Cited by 22 | Viewed by 4280

Abstract

Metformin is a widely used antidiabetic drug for cancer prevention and treatment. However, the overproduction of lactic acid and its inefficiency in cancer therapy limit its application. Here, we demonstrate the synergistic effects of the lactate/GPR81 blockade (3-hydroxy-butyrate, 3-OBA) and metformin on inhibiting [...] Read more.

Metformin is a widely used antidiabetic drug for cancer prevention and treatment. However, the overproduction of lactic acid and its inefficiency in cancer therapy limit its application. Here, we demonstrate the synergistic effects of the lactate/GPR81 blockade (3-hydroxy-butyrate, 3-OBA) and metformin on inhibiting cancer cells growth in vitro. Simultaneously, this combination could inhibit glycolysis and OXPHOS metabolism, as well as inhibiting tumor growth and reducing serum lactate levels in tumor-bearing mice. Interestingly, we observed that this combination could enhance the functions of Jurkat cells in vitro and CD8⁺ T cells in vivo. In addition, considering that 3-OBA could recover the inhibitory effects of metformin on PD-1 expression, we further determined the dual blockade effects of PD-1/PD-L1 and lactate/GPR81 on the antitumor activity of metformin. Our results suggested that this dual blockade strategy could remarkably enhance the anti-tumor effects of metformin, or even lead to tumor regression. In conclusion, our study has proposed a novel and robust strategy for a future application of metformin in cancer treatment. Full article

(This article belongs to the Special Issue Repurposing Drugs for Anti-Cancer Therapy)

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17 pages, 2625 KiB

Open AccessArticle

Repositioning Azelnidipine as a Dual Inhibitor Targeting CD47/SIRPα and TIGIT/PVR Pathways for Cancer Immuno-Therapy

by Xiuman Zhou, Ling Jiao, Yuzhen Qian, Qingyu Dong, Yixuan Sun, Wei V. Zheng, Wenshan Zhao, Wenjie Zhai, Lu Qiu, Yahong Wu, Hongfei Wang, Yanfeng Gao and Junhui Chen

Biomolecules 2021, 11(5), 706; https://doi.org/10.3390/biom11050706 - 10 May 2021

Cited by 21 | Viewed by 3864

Abstract

Strategies boosting both innate and adaptive immunity have great application prospects in cancer immunotherapy. Antibodies dual blocking the innate checkpoint CD47 and adaptive checkpoint PD-L1 or TIGIT could achieve durable anti-tumor effects. However, a small molecule dual blockade of CD47/SIRPα and TIGIT/PVR pathways [...] Read more.

Strategies boosting both innate and adaptive immunity have great application prospects in cancer immunotherapy. Antibodies dual blocking the innate checkpoint CD47 and adaptive checkpoint PD-L1 or TIGIT could achieve durable anti-tumor effects. However, a small molecule dual blockade of CD47/SIRPα and TIGIT/PVR pathways has not been investigated. Here, an elevated expression of CD47 and PVR was observed in tumor tissues and cell lines analyzed with the GEO datasets and by flow cytometry, respectively. Compounds approved by the FDA were screened with the software MOE by docking to the potential binding pockets of SIRPα and PVR identified with the corresponding structural analysis. The candidate compounds were screened by blocking and MST binding assays. Azelnidipine was found to dual block CD47/SIRPα and TIGIT/PVR pathways by co-targeting SIRPα and PVR. In vitro, azelnidipine could enhance the macrophage phagocytosis when co-cultured with tumor cells. In vivo, azelnidipine alone or combined with irradiation could significantly inhibit the growth of MC38 tumors. Azelnidipine also significantly inhibits the growth of CT26 tumors, by enhancing the infiltration and function of CD8⁺ T cell in tumor and systematic immune response in the tumor-draining lymph node and spleen in a CD8⁺ T cell dependent manner. Our research suggests that the anti-hypertensive drug azelnidipine could be repositioned for cancer immunotherapy. Full article

(This article belongs to the Special Issue Repurposing Drugs for Anti-Cancer Therapy)

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Review

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28 pages, 788 KiB

Open AccessReview

Drug Repurposing for Glioblastoma and Current Advances in Drug Delivery—A Comprehensive Review of the Literature

by Safwan Alomari, Irma Zhang, Adrian Hernandez, Caitlin Y. Kraft, Divyaansh Raj, Jayanidhi Kedda and Betty Tyler

Biomolecules 2021, 11(12), 1870; https://doi.org/10.3390/biom11121870 - 13 Dec 2021

Cited by 14 | Viewed by 4659

Abstract

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with an extremely poor prognosis. There is a dire need to develop effective therapeutics to overcome the intrinsic and acquired resistance of GBM to current therapies. The process of developing novel [...] Read more.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with an extremely poor prognosis. There is a dire need to develop effective therapeutics to overcome the intrinsic and acquired resistance of GBM to current therapies. The process of developing novel anti-neoplastic drugs from bench to bedside can incur significant time and cost implications. Drug repurposing may help overcome that obstacle. A wide range of drugs that are already approved for clinical use for the treatment of other diseases have been found to target GBM-associated signaling pathways and are being repurposed for the treatment of GBM. While many of these drugs are undergoing pre-clinical testing, others are in the clinical trial phase. Since GBM stem cells (GSCs) have been found to be a main source of tumor recurrence after surgery, recent studies have also investigated whether repurposed drugs that target these pathways can be used to counteract tumor recurrence. While several repurposed drugs have shown significant efficacy against GBM cell lines, the blood–brain barrier (BBB) can limit the ability of many of these drugs to reach intratumoral therapeutic concentrations. Localized intracranial delivery may help to achieve therapeutic drug concentration at the site of tumor resection while simultaneously minimizing toxicity and side effects. These strategies can be considered while repurposing drugs for GBM. Full article

(This article belongs to the Special Issue Repurposing Drugs for Anti-Cancer Therapy)

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16 pages, 1386 KiB

Open AccessReview

Repurposing Cannabidiol as a Potential Drug Candidate for Anti-Tumor Therapies

by Fei Wang and Gabriele Multhoff

Biomolecules 2021, 11(4), 582; https://doi.org/10.3390/biom11040582 - 15 Apr 2021

Cited by 12 | Viewed by 7758 | Correction

Abstract

In recent years, evidence has accumulated that cannabinoids—especially the non-psychoactive compound, cannabidiol (CBD)—possess promising medical and pharmacological activities that might qualify them as potential anti-tumor drugs. This review is based on multiple studies summarizing different mechanisms for how CBD can target tumor cells [...] Read more.

In recent years, evidence has accumulated that cannabinoids—especially the non-psychoactive compound, cannabidiol (CBD)—possess promising medical and pharmacological activities that might qualify them as potential anti-tumor drugs. This review is based on multiple studies summarizing different mechanisms for how CBD can target tumor cells including cannabinoid receptors or other constituents of the endocannabinoid system, and their complex activation of biological systems that results in the inhibition of tumor growth. CBD also participates in anti-inflammatory activities which are related to tumor progression, as demonstrated in preclinical models. Although the numbers of clinical trials and tested tumor entities are limited, there is clear evidence that CBD has anti-tumor efficacy and is well tolerated in human cancer patients. In summary, it appears that CBD has potential as a neoadjuvant and/or adjuvant drug in therapy for cancer. Full article

(This article belongs to the Special Issue Repurposing Drugs for Anti-Cancer Therapy)

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21 pages, 3520 KiB

Open AccessFeature PaperReview

Against Repurposing Methadone for Glioblastoma Therapy

by Tatjana Vatter, Lukas Klumpp, Katrin Ganser, Nicolai Stransky, Daniel Zips, Franziska Eckert and Stephan M. Huber

Biomolecules 2020, 10(6), 917; https://doi.org/10.3390/biom10060917 - 17 Jun 2020

Cited by 7 | Viewed by 4240

Abstract

Methadone, which is used as maintenance medication for outpatient treatment of opioid dependence or as an analgesic drug, has been suggested by preclinical in vitro and mouse studies to induce cell death and sensitivity to chemo- or radiotherapy in leukemia, glioblastoma, and carcinoma [...] Read more.

Methadone, which is used as maintenance medication for outpatient treatment of opioid dependence or as an analgesic drug, has been suggested by preclinical in vitro and mouse studies to induce cell death and sensitivity to chemo- or radiotherapy in leukemia, glioblastoma, and carcinoma cells. These data together with episodical public reports on long-term surviving cancer patients who use methadone led to a hype of methadone as an anti-cancer drug in social and public media. However, clinical evidence for a tumoricidal effect of methadone is missing and prospective clinical trials, except in colorectal cancer, are not envisaged because of the limited preclinical data available. The present article reviews the pharmacokinetics, potential molecular targets, as well as the evidence for a tumoricidal effect of methadone in view of the therapeutically achievable doses in the brain. Moreover, it provides original in vitro data showing that methadone at clinically relevant concentrations fails to impair clonogenicity or radioresistance of glioblastoma cells. Full article

(This article belongs to the Special Issue Repurposing Drugs for Anti-Cancer Therapy)

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