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28 pages, 5961 KiB

Open AccessArticle

Targeting BRF2 in Cancer Using Repurposed Drugs

by Behnam Rashidieh, Maryam Molakarimi, Ammar Mohseni, Simon Manuel Tria, Hein Truong, Sriganesh Srihari, Rachael C. Adams, Mathew Jones, Pascal H. G. Duijf, Murugan Kalimutho and Kum Kum Khanna

Cancers 2021, 13(15), 3778; https://doi.org/10.3390/cancers13153778 - 27 Jul 2021

Cited by 5 | Viewed by 2700

Abstract

The overexpression of BRF2, a selective subunit of RNA polymerase III, has been shown to be crucial in the development of several types of cancers, including breast cancer and lung squamous cell carcinoma. Predominantly, BRF2 acts as a central redox-sensing transcription factor (TF) [...] Read more.

The overexpression of BRF2, a selective subunit of RNA polymerase III, has been shown to be crucial in the development of several types of cancers, including breast cancer and lung squamous cell carcinoma. Predominantly, BRF2 acts as a central redox-sensing transcription factor (TF) and is involved in rescuing oxidative stress (OS)-induced apoptosis. Here, we showed a novel link between BRF2 and the DNA damage response. Due to the lack of BRF2-specific inhibitors, through virtual screening and molecular dynamics simulation, we identified potential drug candidates that interfere with BRF2-TATA-binding Protein (TBP)-DNA complex interactions based on binding energy, intermolecular, and torsional energy parameters. We experimentally tested bexarotene as a potential BRF2 inhibitor. We found that bexarotene (Bex) treatment resulted in a dramatic decline in oxidative stress and Tert-butylhydroquinone (tBHQ)-induced levels of BRF2 and consequently led to a decrease in the cellular proliferation of cancer cells which may in part be due to the drug pretreatment-induced reduction of ROS generated by the oxidizing agent. Our data thus provide the first experimental evidence that BRF2 is a novel player in the DNA damage response pathway and that bexarotene can be used as a potential inhibitor to treat cancers with the specific elevation of oxidative stress. Full article

(This article belongs to the Special Issue Small Molecule Regulators of Cancer-Related Proteins: Where Are We in Precision Medicine?)

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19 pages, 2372 KiB

Open AccessArticle

Suppression of Breast Cancer by Small Molecules That Block the Prolactin Receptor

by Dana C. Borcherding, Eric R. Hugo, Sejal R. Fox, Eric M. Jacobson, Brian G. Hunt, Edward J. Merino and Nira Ben-Jonathan

Cancers 2021, 13(11), 2662; https://doi.org/10.3390/cancers13112662 - 28 May 2021

Cited by 12 | Viewed by 2797

Abstract

Prolactin (PRL) is a protein hormone which in humans is secreted by pituitary lactotrophs as well as by many normal and malignant non-pituitary sites. Many lines of evidence demonstrate that both circulating and locally produced PRL increase breast cancer (BC) growth and metastases [...] Read more.

Prolactin (PRL) is a protein hormone which in humans is secreted by pituitary lactotrophs as well as by many normal and malignant non-pituitary sites. Many lines of evidence demonstrate that both circulating and locally produced PRL increase breast cancer (BC) growth and metastases and confer chemoresistance. Our objective was to identify and then characterize small molecules that block the tumorigenic actions of PRL in BC. We employed three cell-based assays in high throughput screening (HTS) of 51,000 small molecules and identified two small molecule inhibitors (SMIs), named SMI-1 and SMI-6. Both compounds bound to the extracellular domain (ECD) of the PRL receptor (PRLR) at 1–3 micromolar affinity and abrogated PRL-induced breast cancer cell (BCC) invasion and malignant lymphocyte proliferation. SMI-6 effectively reduced the viability of multiple BCC types, had much lower activity against various non-malignant cells, displayed high selectivity, and showed no apparent in vitro or in vivo toxicity. In athymic nude mice, SMI-6 rapidly and dramatically suppressed the growth of PRL-expressing BC xenografts. This report represents a pre-clinical phase of developing novel anti-cancer agents with the potential to become effective therapeutics in breast cancer patients. Full article

(This article belongs to the Special Issue Small Molecule Regulators of Cancer-Related Proteins: Where Are We in Precision Medicine?)

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24 pages, 48156 KiB

Open AccessArticle

Targeting p53 for Melanoma Treatment: Counteracting Tumour Proliferation, Dissemination and Therapeutic Resistance

by Joana B. Loureiro, Liliana Raimundo, Juliana Calheiros, Carla Carvalho, Valentina Barcherini, Nuno R. Lima, Célia Gomes, Maria Inês Almeida, Marco G. Alves, José Luís Costa, Maria M. M. Santos and Lucília Saraiva

Cancers 2021, 13(7), 1648; https://doi.org/10.3390/cancers13071648 - 01 Apr 2021

Cited by 11 | Viewed by 4695

Abstract

Melanoma is the deadliest form of skin cancer, primarily due to its high metastatic propensity and therapeutic resistance in advanced stages. The frequent inactivation of the p53 tumour suppressor protein in melanomagenesis may predict promising outcomes for p53 activators in melanoma therapy. Herein, [...] Read more.

Melanoma is the deadliest form of skin cancer, primarily due to its high metastatic propensity and therapeutic resistance in advanced stages. The frequent inactivation of the p53 tumour suppressor protein in melanomagenesis may predict promising outcomes for p53 activators in melanoma therapy. Herein, we aimed to investigate the antitumor potential of the p53-activating agent SLMP53-2 against melanoma. Two- and three-dimensional cell cultures and xenograft mouse models were used to unveil the antitumor activity and the underlying molecular mechanism of SLMP53-2 in melanoma. SLMP53-2 inhibited the growth of human melanoma cells in a p53-dependent manner through induction of cell cycle arrest and apoptosis. Notably, SLMP53-2 induced p53 stabilization by disrupting the p53–MDM2 interaction, enhancing p53 transcriptional activity. It also promoted the expression of p53-regulated microRNAs (miRNAs), including miR-145 and miR-23a. Moreover, it displayed anti-invasive and antimigratory properties in melanoma cells by inhibiting the epithelial-to-mesenchymal transition (EMT), angiogenesis and extracellular lactate production. Importantly, SLMP53-2 did not induce resistance in melanoma cells. Additionally, it synergized with vemurafenib, dacarbazine and cisplatin, and resensitized vemurafenib-resistant cells. SLMP53-2 also exhibited antitumor activity in human melanoma xenograft mouse models by repressing cell proliferation and EMT while stimulating apoptosis. This work discloses the p53-activating agent SLMP53-2 which has promising therapeutic potential in advanced melanoma, either as a single agent or in combination therapy. By targeting p53, SLMP53-2 may counteract major features of melanoma aggressiveness. Full article

(This article belongs to the Special Issue Small Molecule Regulators of Cancer-Related Proteins: Where Are We in Precision Medicine?)

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23 pages, 2548 KiB

Open AccessArticle

Novel Thiosemicarbazones Sensitize Pediatric Solid Tumor Cell-Types to Conventional Chemotherapeutics through Multiple Molecular Mechanisms

by Silvia Paukovcekova, Jan Skoda, Jakub Neradil, Erika Mikulenkova, Petr Chlapek, Jaroslav Sterba, Des R. Richardson and Renata Veselska

Cancers 2020, 12(12), 3781; https://doi.org/10.3390/cancers12123781 - 15 Dec 2020

Cited by 5 | Viewed by 2418

Abstract

Combining low-dose chemotherapies is a strategy for designing less toxic and more potent childhood cancer treatments. We examined the effects of combining the novel thiosemicarbazones, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), or its analog, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), with the standard chemotherapies, celecoxib (CX), etoposide (ETO), or temozolomide [...] Read more.

Combining low-dose chemotherapies is a strategy for designing less toxic and more potent childhood cancer treatments. We examined the effects of combining the novel thiosemicarbazones, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), or its analog, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), with the standard chemotherapies, celecoxib (CX), etoposide (ETO), or temozolomide (TMZ). These combinations were analyzed for synergism to inhibit proliferation of three pediatric tumor cell-types, namely osteosarcoma (Saos-2), medulloblastoma (Daoy) and neuroblastoma (SH-SY5Y). In terms of mechanistic dissection, this study discovered novel thiosemicarbazone targets not previously identified and which are important for considering possible drug combinations. In this case, DpC and Dp44mT caused: (1) up-regulation of a major protein target of CX, namely cyclooxygenase-2 (COX-2); (2) down-regulation of the DNA repair protein, O⁶-methylguanine DNA methyltransferase (MGMT), which is known to affect TMZ resistance; (3) down-regulation of mismatch repair (MMR) proteins, MSH2 and MSH6, in Daoy and SH-SY5Y cells; and (4) down-regulation in all three cell-types of the MMR repair protein, MLH1, and also topoisomerase 2α (Topo2α), the latter of which is an ETO target. While thiosemicarbazones up-regulate the metastasis suppressor, NDRG1, in adult cancers, it is demonstrated herein for the first time that they induce NDRG1 in all three pediatric tumor cell-types, validating its role as a potential target. In fact, siRNA studies indicated that NDRG1 was responsible for MGMT down-regulation that may prevent TMZ resistance. Examining the effects of combining thiosemicarbazones with CX, ETO, or TMZ, the most promising synergism was obtained using CX. Of interest, a positive relationship was observed between NDRG1 expression of the cell-type and the synergistic activity observed in the combination of thiosemicarbazones and CX. These studies identify novel thiosemicarbazone targets relevant to childhood cancer combination chemotherapy. Full article

(This article belongs to the Special Issue Small Molecule Regulators of Cancer-Related Proteins: Where Are We in Precision Medicine?)

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Review

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24 pages, 2598 KiB

Open AccessReview

Exploiting DNA Damage Repair in Precision Cancer Therapy: BRCA1 as a Prime Therapeutic Target

by Liliana Raimundo, Juliana Calheiros and Lucília Saraiva

Cancers 2021, 13(14), 3438; https://doi.org/10.3390/cancers13143438 - 09 Jul 2021

Cited by 11 | Viewed by 5143

Abstract

Precision medicine aims to identify specific molecular alterations, such as driver mutations, allowing tailored and effective anticancer therapies. Poly(ADP)-ribose polymerase inhibitors (PARPi) are the prototypical example of targeted therapy, exploiting the inability of cancer cells to repair DNA damage. Following the concept of [...] Read more.

Precision medicine aims to identify specific molecular alterations, such as driver mutations, allowing tailored and effective anticancer therapies. Poly(ADP)-ribose polymerase inhibitors (PARPi) are the prototypical example of targeted therapy, exploiting the inability of cancer cells to repair DNA damage. Following the concept of synthetic lethality, PARPi have gained great relevance, particularly in BRCA1 dysfunctional cancer cells. In fact, BRCA1 mutations culminate in DNA repair defects that can render cancer cells more vulnerable to therapy. However, the efficacy of these drugs has been greatly affected by the occurrence of resistance due to multi-connected DNA repair pathways that may compensate for each other. Hence, the search for additional effective agents targeting DNA damage repair (DDR) is of crucial importance. In this context, BRCA1 has assumed a central role in developing drugs aimed at inhibiting DNA repair activity. Collectively, this review provides an in-depth understanding of the biology and regulatory mechanisms of DDR pathways, highlighting the potential of DDR-associated molecules, particularly BRCA1 and its interconnected partners, in precision cancer medicine. It also affords an overview about what we have achieved and a reflection on how much remains to be done in this field, further addressing encouraging clues for the advance of DDR targeted therapy. Full article

(This article belongs to the Special Issue Small Molecule Regulators of Cancer-Related Proteins: Where Are We in Precision Medicine?)

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38 pages, 8812 KiB

Open AccessReview

Structural and Drug Targeting Insights on Mutant p53

by Ana Sara Gomes, Helena Ramos, Alberto Inga, Emília Sousa and Lucília Saraiva

Cancers 2021, 13(13), 3344; https://doi.org/10.3390/cancers13133344 - 03 Jul 2021

Cited by 34 | Viewed by 5351

Abstract

p53 is a transcription factor with a pivotal role in cell homeostasis and fate. Its impairment is a major event in tumor onset and development. In fact, about half of human cancers bear TP53 mutations that not only halt the normal function of [...] Read more.

p53 is a transcription factor with a pivotal role in cell homeostasis and fate. Its impairment is a major event in tumor onset and development. In fact, about half of human cancers bear TP53 mutations that not only halt the normal function of p53, but also may acquire oncogenic gain of functions that favor tumorigenesis. Although considered undruggable for a long time, evidence has proven the capability of many compounds to restore a wild-type (wt)-like function to mutant p53 (mutp53). However, they have not reached the clinic to date. Structural studies have strongly contributed to the knowledge about p53 structure, stability, dynamics, function, and regulation. Importantly, they have afforded relevant insights into wt and mutp53 pharmacology at molecular levels, fostering the design and development of p53-targeted anticancer therapies. Herein, we provide an integrated view of mutp53 regulation, particularly focusing on mutp53 structural traits and on targeting agents capable of its reactivation, including their biological, biochemical and biophysical features. With this, we expect to pave the way for the development of improved small molecules that may advance precision cancer therapy by targeting p53. Full article

(This article belongs to the Special Issue Small Molecule Regulators of Cancer-Related Proteins: Where Are We in Precision Medicine?)

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43 pages, 1734 KiB

Open AccessReview

Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors

by Gabriel LaPlante and Wei Zhang

Cancers 2021, 13(12), 3079; https://doi.org/10.3390/cancers13123079 - 20 Jun 2021

Cited by 40 | Viewed by 8920

Abstract

The ubiquitin-proteasome system (UPS) is a critical regulator of cellular protein levels and activity. It is, therefore, not surprising that its dysregulation is implicated in numerous human diseases, including many types of cancer. Moreover, since cancer cells exhibit increased rates of protein turnover, [...] Read more.

The ubiquitin-proteasome system (UPS) is a critical regulator of cellular protein levels and activity. It is, therefore, not surprising that its dysregulation is implicated in numerous human diseases, including many types of cancer. Moreover, since cancer cells exhibit increased rates of protein turnover, their heightened dependence on the UPS makes it an attractive target for inhibition via targeted therapeutics. Indeed, the clinical application of proteasome inhibitors in treatment of multiple myeloma has been very successful, stimulating the development of small-molecule inhibitors targeting other UPS components. On the other hand, while the discovery of potent and selective chemical compounds can be both challenging and time consuming, the area of targeted protein degradation through utilization of the UPS machinery has seen promising developments in recent years. The repertoire of proteolysis-targeting chimeras (PROTACs), which employ E3 ligases for the degradation of cancer-related proteins via the proteasome, continues to grow. In this review, we will provide a thorough overview of small-molecule UPS inhibitors and highlight advancements in the development of targeted protein degradation strategies for cancer therapeutics. Full article

(This article belongs to the Special Issue Small Molecule Regulators of Cancer-Related Proteins: Where Are We in Precision Medicine?)

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26 pages, 789 KiB

Open AccessReview

Small-Molecule Inhibitors (SMIs) as an Effective Therapeutic Strategy for Endometrial Cancer

by Cristina Megino-Luque, Cristian Pablo Moiola, Clara Molins-Escuder, Carlos López-Gil, Antonio Gil-Moreno, Xavier Matias-Guiu, Eva Colas and Núria Eritja

Cancers 2020, 12(10), 2751; https://doi.org/10.3390/cancers12102751 - 24 Sep 2020

Cited by 13 | Viewed by 3387

Abstract

Endometrial cancer (EC) is the sixth most common cancer in women. A continued number of low-risk EC patients at diagnosis, as well as patients diagnosed with advanced-stage disease, will experience an aggressive disease. Unfortunately, those patients will present recurrence or overt dissemination. Systemic [...] Read more.

Endometrial cancer (EC) is the sixth most common cancer in women. A continued number of low-risk EC patients at diagnosis, as well as patients diagnosed with advanced-stage disease, will experience an aggressive disease. Unfortunately, those patients will present recurrence or overt dissemination. Systemic cytotoxic chemotherapy treatment on advanced, recurrent, or metastatic EC patients has shown poor results, with median survival rates of less than one year, and median progression-free survival rates of four months. Therefore, the search for innovative and alternative drugs or the development of combinatorial therapies involving new targeted drugs and standard regimens is imperative. Over the last few decades, some small-molecule inhibitors have been introduced in the clinics for cancer treatment, but only a few have been approved by the Food and Drug Administration (FDA) for EC treatment. In the present review, we present the current state and future prospects of small-molecule inhibitors on EC treatment, both alone and in combination. Full article

(This article belongs to the Special Issue Small Molecule Regulators of Cancer-Related Proteins: Where Are We in Precision Medicine?)

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