Advances in heterocycles as DNA intercalating cancer drugs

The insertion of a molecule between the bases of DNA is known as intercalation. A molecule is able to interact with DNA in different ways. DNA intercalators are generally aromatic, planar, and polycyclic. In chemotherapeutic treatment, to suppress DNA replication in cancer cells, intercalators are used. In this article, we discuss the anticancer activity of 10 intensively studied DNA intercalators as drugs. The list includes proflavine, ethidium bromide, doxorubicin, dactinomycin, bleomycin, epirubicin, mitoxantrone, ellipticine, elinafide, and echinomycin. Considerable structural diversities are seen in these molecules. Besides, some examples of the metallo-intercalators are presented at the end of the chapter. These molecules have other crucial properties that are also useful in the treatment of cancers. The successes and limitations of these molecules are also presented.

CRISPR screens uncover protective effect of PSTK as a regulator of chemotherapy-induced ferroptosis in hepatocellular carcinoma

Background Hepatocellular carcinoma (HCC) is among the most common forms of cancer and is associated with poor patient outcomes. The emergence of therapeutic resistance has hampered the efficacy of targeted treatments employed to treat HCC patients to date. In this study, we conducted a series of CRISPR/Cas9 screens to identify genes associated with synthetic lethality capable of improving HCC patient clinical responses. Methods CRISPR-based loss-of-function genetic screens were used to target 18,053 protein-coding genes in HCC cells to identify chemotherapy-related synthetic lethal genes in these cells. Synergistic effects were analyzed through in vitro and in vivo analyses, while related mechanisms were explored through RNA-seq and metabolomics analyses. Potential inhibitors of identified genetic targets were selected through high-throughput virtual screening. Results The inhibition of phosphoseryl-tRNA kinase (PSTK) was found to increase HCC cell sensitivity to chemotherapeutic treatment. PSTK was associated with the suppression of chemotherapy-induced ferroptosis in HCC cells, and the depletion of PSTK resulted in the inactivation of glutathione peroxidative 4 (GPX4) and the disruption of glutathione (GSH) metabolism owing to the inhibition of selenocysteine and cysteine synthesis, thus enhancing the induction of ferroptosis upon targeted chemotherapeutic treatment. Punicalin, an agent used to treat hepatitis B virus (HBV), was identified as a possible PSTK inhibitor that exhibited synergistic efficacy when applied together with Sorafenib to treat HCC in vitro and in vivo. Conclusions These results highlight a key role for PSTK as a mediator of resistance to targeted therapeutic treatment in HCC cells that functions by suppressing ferroptotic induction. PSTK inhibitors may thus represent ideal candidates for overcoming drug resistance in HCC.

Clinical case of angiosarcoma of pericardium and pleura

Primary heart tumors are an extremely rare pathology, previously detected only by autopsy data and detected in 0.001%-0.03% of cases. Primary angiosarcomas of the pericardium are even more rare and are presented in the literature with isolated descriptions. The article describes a clinical case of epithelioid angiosarcoma of the pericardium and pleura of high malignancy in a 57-year-old man. The diagnosis was confirmed by immunohistochemical examination and positron emission tomography. For today, chemotherapeutic treatment of angiosarcomas localized in the chest cavity is a palliative treatment method. In this patient, the most effective scheme was the one containing anthracyclines (doxorubicin). Despite the ongoing therapy, the patient died 15 months after the diagnosis was made, with increasing signs of respiratory and heart failure. Thus, when patients, especially young and middle-aged men, show signs of hydropericardium without established etiological prerequisites, it is necessary to remember about the possibility of developing a primary malignant tumor of the heart and / or pericardium as the cause of this condition and include it in the standard diagnostic search.

The Influence of BCL6 on the WNT Pathway in Glioblastoma Therapy Resistance

<p>Glioblastoma is a devastating disease with a median survival of 18 months from diagnosis and a 5 years survival rate of only 10%. The gold standard of treatment for glioblastoma is surgical resection followed by chemotherapeutic treatment with Temozolomide, a DNA alkylating agent, and irradiation around the remaining tumour margins. These treatments are both designed to create DNA damage to the cancerous cells, causing the cell cycle to halt, and result in apoptosis. This treatment does extend patients life for a few months, however glioblastoma cells quickly become resistant to therapy, and disease is always fatal. The anti-apoptotic protein BCL6, confers resistance to apoptosis in response to DNA damage and has been shown to be upregulated in Glioblastoma in response to DNA damaging chemotherapy and irradiation. This upregulation has been hypothesised to increase resistance to these therapies. By minimizing resistance to the standard therapies, the outlook for sufferers of glioblastoma could be greatly improved. Dysregulation of the WNT pathway has also been shown to be very important in carcinogenesis of glioblastoma and is responsible for the diffuse nature of the tumour which makes total resection nearly impossible. An RNA-seq screen was carried out on a glioblastoma cell line in which BCL6 was inhibited using the small molecule inhibitor FX1. This resulted in a change in expression of a large number of WNT related genes. This indicates that there is a link between BCL6 and the WNT pathway. Changes in expression in the WNT genes DKK1, WNT5a and WNT5b were validated. Experiments were carried out to investigate the effects of chemotherapy and BCL6 inhibition on both the canonical and non-canonical WNT pathways. It was found that BCL6 has an influence of the level of activity of the canonical WNT pathway. It also influences migration, the cell cycle, and clonogenicity. Understanding this link between WNT and BCL6 could be crucial in finding an effective treatment for glioblastoma.</p>

The Influence of BCL6 on the WNT Pathway in Glioblastoma Therapy Resistance

<p>Glioblastoma is a devastating disease with a median survival of 18 months from diagnosis and a 5 years survival rate of only 10%. The gold standard of treatment for glioblastoma is surgical resection followed by chemotherapeutic treatment with Temozolomide, a DNA alkylating agent, and irradiation around the remaining tumour margins. These treatments are both designed to create DNA damage to the cancerous cells, causing the cell cycle to halt, and result in apoptosis. This treatment does extend patients life for a few months, however glioblastoma cells quickly become resistant to therapy, and disease is always fatal. The anti-apoptotic protein BCL6, confers resistance to apoptosis in response to DNA damage and has been shown to be upregulated in Glioblastoma in response to DNA damaging chemotherapy and irradiation. This upregulation has been hypothesised to increase resistance to these therapies. By minimizing resistance to the standard therapies, the outlook for sufferers of glioblastoma could be greatly improved. Dysregulation of the WNT pathway has also been shown to be very important in carcinogenesis of glioblastoma and is responsible for the diffuse nature of the tumour which makes total resection nearly impossible. An RNA-seq screen was carried out on a glioblastoma cell line in which BCL6 was inhibited using the small molecule inhibitor FX1. This resulted in a change in expression of a large number of WNT related genes. This indicates that there is a link between BCL6 and the WNT pathway. Changes in expression in the WNT genes DKK1, WNT5a and WNT5b were validated. Experiments were carried out to investigate the effects of chemotherapy and BCL6 inhibition on both the canonical and non-canonical WNT pathways. It was found that BCL6 has an influence of the level of activity of the canonical WNT pathway. It also influences migration, the cell cycle, and clonogenicity. Understanding this link between WNT and BCL6 could be crucial in finding an effective treatment for glioblastoma.</p>

Limitations and Possibilities of Transarterial Chemotherapeutic Treatment of Hepatocellular Carcinoma

Because diagnostic tools for discriminating between hepatocellular carcinoma (HCC) and advanced cirrhosis are poor, HCC is often detected in a stage where transarterial chemoembolization (TACE) is the best treatment option, even though it provides a poor survival gain. Despite having been used worldwide for several decades, TACE still has many limitations. First, there is a vast heterogeneity in the cellular composition and metabolism of HCCs as well as in the patient population, which renders it difficult to identify patients who would benefit from TACE. Often the delivered drug does not penetrate sufficiently selectively and deeply into the tumour and the drug delivery system is not releasing the drug at an optimal clinical rate. In addition, therapeutic effectiveness is limited by the crosstalk between the tumour cells and components of the cirrhotic tumour microenvironment. To improve this widely used treatment of one of our most common and deadly cancers, we need to better understand the complex interactions between drug delivery, local pharmacology, tumour targeting mechanisms, liver pathophysiology, patient and tumour heterogeneity, and resistance mechanisms. This review provides a novel and important overview of clinical data and discusses the role of the tumour microenvironment and lymphatic system in the cirrhotic liver, its potential response to TACE, and current and possible novel DDSs for locoregional treatment.

Cranial and Spinal Metastasis of a Nonfunctioning Pituitary Adenoma: Report of a Case

Pituitary carcinoma is a rare disease with surgical, radiotherapeutic, and chemotherapeutic treatment options. We present the case of a female patient diagnosed with a nonfunctioning pituitary adenoma who underwent several surgical procedures, radiations, and chemotherapeutic treatments with various substances. Sixteen years after the first diagnosis, a cranial and spinal metastatic spread of the tumor occurred. We opted for an individual therapy based on anecdotal evidence. Unfortunately, the recommended off-label treatment with a somatostatin analog substance was never given due to bureaucratic delays. This case report is about the challenging aspects of individual decision-making in rare neurosurgical diseases.

Metastatic melanomas: Treatment overview

Melanomas especially metastatic melanoma chemotherapeutic treatment has been discussed in the review article. The recent advancement in the chemotherapy being Immunotherapy targeted therapy, combination therapy, targeted therapy, combination therapies and biochemotherpies all of which have been discussed in this review article.

Metal Sulfide Semiconductor Nanomaterials and Polymer Microgels for Biomedical Applications

The development of nanomaterials with therapeutic and/or diagnostic properties has been an active area of research in biomedical sciences over the past decade. Nanomaterials have been identified as significant medical tools with potential therapeutic and diagnostic capabilities that are practically impossible to accomplish using larger molecules or bulk materials. Fabrication of nanomaterials is the most effective platform to engineer therapeutic agents and delivery systems for the treatment of cancer. This is mostly due to the high selectivity of nanomaterials for cancerous cells, which is attributable to the porous morphology of tumour cells which allows nanomaterials to accumulate more in tumour cells more than in normal cells. Nanomaterials can be used as potential drug delivery systems since they exist in similar scale as proteins. The unique properties of nanomaterials have drawn a lot of interest from researchers in search of new chemotherapeutic treatment for cancer. Metal sulfide nanomaterials have emerged as the most used frameworks in the past decade, but they tend to aggregate because of their high surface energy which triggers the thermodynamically favoured interaction. Stabilizing agents such as polymer and microgels have been utilized to inhibit the particles from any aggregations. In this review, we explore the development of metal sulfide polymer/microgel nanocomposites as therapeutic agents against cancerous cells.

Synthesis of Aminooxy Glycoside Derivatives of the Outer Core Domain of Pseudomonas aeruginosa Lipopolysaccharide

Pseudomonas aeruginosa is a highly prevalent gram-negative bacterium that is becoming more difficult to treat because of increasing antibiotic resistance. As chemotherapeutic treatment options diminish, there is an increased need for vaccines. However, the creation of an effective P. aeruginosa vaccine has been elusive despite intensive efforts. Thus, new paradigms for vaccine antigens should be explored to develop effective vaccines. In these studies, we have focused on the synthesis of two L-rhamnose–bearing epitopes common to glycoforms I and II of the outer core domain of Pseudomonas aeruginosa lipopolysaccharide, α-L-Rha-(1→6)-α-D-Glc-(1→4)-α-D-GalN-(Ala)-α-aminooxy (3) and α-L-Rha-(1→3)-β-D-Glc-(1→3)-α-D-GalN-(Ala)-α-aminooxy (4), respectively. The target trisaccharides were both prepared starting from a suitably protected galactosamine glycoside, followed by successive deprotection and glycosylation with suitably protected D-glucose and L-rhamnose thioglycosides. Global deprotection resulted in the formation of targets 3 and 4 in 22 and 35% yield each. Care was required to modify basic reaction conditions to avoid early deprotection of the N-oxysuccinamido group. In summary, trisaccharides related to the L-rhamnose–bearing epitopes common to glycoforms I and II of the outer core domain of Pseudomonas aeruginosa lipopolysaccharide have been prepared as their aminooxy glycosides. The latter are expected to be useful in chemoselective oxime-based bioconjugation reactions to form Pseudomonas aeruginosa vaccines.