Ivermectin: Potential Repurposing of a Versatile Antiparasitic as a Novel Anticancer

Drug repositioning is a alternative strategy to discover and develop anticancer drugs based on identification of new mechanisms of actions and indications for existing compounds. Ivermectin belongs to the avermectin group of compounds, a series of 16-membered macrocyclic lactone moieties discovered in 1967 and FDA-approved for human use since 1987. Ivermectin has since been used by millions of people worldwide, and have demonstrated a wide margin of clinical safety. Here we summarize the in vitro and in vivo evidence demonstrating ivermectin\u27s potential as a multitargeting anticancer drug that exerts antitumor effects against different tumor types. Notably, the in vitro and in vivo antitumor activities of ivermectin are achieved at concentrations that can be clinically achieved based on human pharmacokinetic studies done in the clinical studies. Moreover, repurposed ivermectin safety has been well established recently in clinical studies against COVID-19. Consequently, we believe that ivermectin is an excellent potential candidate drug that can be repurposed for cancer and deserves rigorous evaluation against a variety of cancers in well-designed clinical trials

The Epigenetic Origin of Aneuploidy

Theodore Boveri, eminent German pathologist, observed aneuploidy in cancer cells more than a century ago and suggested that cancer cells derived from a single progenitor cell that acquires the potential for uncontrolled continuous proliferation. Currently, it is well known that aneuploidy is observed in virtually all cancers. Gain and loss of chromosomal material in neoplastic cells is considered to be a process of diversification that leads to survival of the fittest clones. According to Darwin’s theory of evolution, the environment determines the grounds upon which selection takes place and the genetic characteristics necessary for better adaptation. This concept can be applied to the carcinogenesis process, connecting the ability of cancer cells to adapt to different environments and to resist chemotherapy, genomic instability being the driving force of tumor development and progression. What causes this genome instability? Mutations have been recognized for a long time as the major source of genome instability in cancer cells. Nevertheless, an alternative hypothesis suggests that aneuploidy is a primary cause of genome instability rather than solely a simple consequence of the malignant transformation process. Whether genome instability results from mutations or from aneuploidy is not a matter of discussion in this review. It is most likely both phenomena are intimately related; however, we will focus on the mechanisms involved in aneuploidy formation and more specifically on the epigenetic origin of aneuploid cells. Epigenetic inheritance is defined as cellular information—other than the DNA sequence itself—that is heritable during cell division. DNA methylation and histone modifications comprise two of the main epigenetic modifications that are important for many physiological and pathological conditions, including cancer. Aberrant DNA methylation is the most common molecular cancer-cell lesion, even more frequent than gene mutations; tumor suppressor gene silencing by CpG island promoter hypermethylation is perhaps the most frequent epigenetic modification in cancer cells. Epigenetic characteristics of cells may be modified by several factors including environmental exposure, certain nutrient deficiencies, radiation, etc. Some of these alterations have been correlated with the formation of aneuploid cells in vivo. A growing body of evidence suggests that aneuploidy is produced and caused by chromosomal instability. We propose and support in this manuscript that not only genetics but also epigenetics, contribute in a major fashion to aneuploid cell formation

The Epigenetic Origin of Aneuploidy

Theodore Boveri, eminent German pathologist, observed aneuploidy in cancer cells more than a century ago and suggested that cancer cells derived from a single progenitor cell that acquires the potential for uncontrolled continuous proliferation. Currently, it is well known that aneuploidy is observed in virtually all cancers. Gain and loss of chromosomal material in neoplastic cells is considered to be a process of diversification that leads to survival of the fittest clones. According to Darwin’s theory of evolution, the environment determines the grounds upon which selection takes place and the genetic characteristics necessary for better adaptation. This concept can be applied to the carcinogenesis process, connecting the ability of cancer cells to adapt to different environments and to resist chemotherapy, genomic instability being the driving force of tumor development and progression. What causes this genome instability? Mutations have been recognized for a long time as the major source of genome instability in cancer cells. Nevertheless, an alternative hypothesis suggests that aneuploidy is a primary cause of genome instability rather than solely a simple consequence of the malignant transformation process. Whether genome instability results from mutations or from aneuploidy is not a matter of discussion in this review. It is most likely both phenomena are intimately related; however, we will focus on the mechanisms involved in aneuploidy formation and more specifically on the epigenetic origin of aneuploid cells. Epigenetic inheritance is defined as cellular information—other than the DNA sequence itself—that is heritable during cell division. DNA methylation and histone modifications comprise two of the main epigenetic modifications that are important for many physiological and pathological conditions, including cancer. Aberrant DNA methylation is the most common molecular cancer-cell lesion, even more frequent than gene mutations; tumor suppressor gene silencing by CpG island promoter hypermethylation is perhaps the most frequent epigenetic modification in cancer cells. Epigenetic characteristics of cells may be modified by several factors including environmental exposure, certain nutrient deficiencies, radiation, etc. Some of these alterations have been correlated with the formation of aneuploid cells in vivo. A growing body of evidence suggests that aneuploidy is produced and caused by chromosomal instability. We propose and support in this manuscript that not only genetics but also epigenetics, contribute in a major fashion to aneuploid cell formation

Epigenetics of cervical cancer. An overview and therapeutic perspectives

Cervical cancer remains one of the greatest killers of women worldwide. It is difficult to foresee a dramatic increase in cure rate even with the most optimal combination of cytotoxic drugs, surgery, and radiation; therefore, testing of molecular targeted therapies against this malignancy is highly desirable. A number of epigenetic alterations occur during all stages of cervical carcinogenesis in both human papillomavirus and host cellular genomes, which include global DNA hypomethylation, hypermetylation of key tumor suppressor genes, and histone modifications. The reversible nature of epigenetic changes constitutes a target for transcriptional therapies, namely DNA methylation and histone deacetylase inhibitors. To date, studies in patients with cervical cancer have demonstrated the feasibility of reactivating the expression of hypermethylated and silenced tumor suppressor genes as well as the hyperacetylating and inhibitory effect upon histone deacetylase activity in tumor tissues after treatment with demethylating and histone deacetylase inhibitors. In addition, detection of epigenetic changes in cytological smears, serum DNA, and peripheral blood are of potential interest for development of novel biomolecular markers for early detection, prediction of response, and prognosis

Reviving Lonidamine and 6-Diazo-5-oxo-L-norleucine to Be Used in Combination for Metabolic Cancer Therapy

Abnormal metabolism is another cancer hallmark. The two most characterized altered metabolic pathways are high rates of glycolysis and glutaminolysis, which are natural targets for cancer therapy. Currently, a number of newer compounds to block glycolysis and glutaminolysis are being developed; nevertheless, lonidamine and 6-diazo-5-oxo-L-norleucine (DON) are two old drugs well characterized as inhibitors of glycolysis and glutaminolysis, respectively, whose clinical development was abandoned years ago when the importance of cancer metabolism was not fully appreciated and clinical trial methodology was less developed. In this review, a PubMed search using the words lonidamine and 6-diazo-5-oxo-L-norleucine (DON) was undertaken to analyse existing information on the preclinical and clinical studies of these drugs for cancer treatment. Data show that they exhibit antitumor effects; besides there is also the suggestion that they are synergistic. We conclude that lonidamine and DON are safe and potentially effective drugs that need to be reevaluated in combination as metabolic therapy of cancer

The prince and the pauper. A tale of anticancer targeted agents

Cancer rates are set to increase at an alarming rate, from 10 million new cases globally in 2000 to 15 million in 2020. Regarding the pharmacological treatment of cancer, we currently are in the interphase of two treatment eras. The so-called pregenomic therapy which names the traditional cancer drugs, mainly cytotoxic drug types, and post-genomic era-type drugs referring to rationally-based designed. Although there are successful examples of this newer drug discovery approach, most target-specific agents only provide small gains in symptom control and/or survival, whereas others have consistently failed in the clinical testing. There is however, a characteristic shared by these agents: -their high cost-. This is expected as drug discovery and development is generally carried out within the commercial rather than the academic realm. Given the extraordinarily high therapeutic drug discovery-associated costs and risks, it is highly unlikely that any single public-sector research group will see a novel chemical "probe" become a "drug". An alternative drug development strategy is the exploitation of established drugs that have already been approved for treatment of non-cancerous diseases and whose cancer target has already been discovered. This strategy is also denominated drug repositioning, drug repurposing, or indication switch. Although traditionally development of these drugs was unlikely to be pursued by Big Pharma due to their limited commercial value, biopharmaceutical companies attempting to increase productivity at present are pursuing drug repositioning. More and more companies are scanning the existing pharmacopoeia for repositioning candidates, and the number of repositioning success stories is increasing. Here we provide noteworthy examples of known drugs whose potential anticancer activities have been highlighted, to encourage further research on these known drugs as a means to foster their translation into clinical trials utilizing the more limited public-sector resources. If these drug types eventually result in being effective, it follows that they could be much more affordable for patients with cancer; therefore, their contribution in terms of reducing cancer mortality at the global level would be greater

The effects of DNA methylation and histone deacetylase inhibitors upon the human papillomavirus early genes expression in cervical cancer. An in vitro and clinical study

BACKGROUND: The methylation status at the human papilloma virus (HPV) genome found in pre-invasive and invasive cervical lesions suggests that neoplastic transformation can be suppressed by gene hypermethylation, whereas hypomethylation accompanies or causes cancer progression; hence, epigenetic therapy aimed at reactivating cellular suppressor-gene expression has the potential to act as a tumor promoter by enhancing HPV oncoprotein expression in HPV-related malignancies. The objective of this study was to determine the influence of hydralazine and valproate on HPV oncogene expression in cervical cancer cell lines and the primary tumors of patients undergoing treatment with hydralazine and valproate. RESULTS: Overall, hydralazine and valproate either alone or combined exerted a growth inhibitory effect on cervical cancer cell lines. A cell line-specific up-regulating effect was observed on E6/E7 gene expression, which in general correlated with DNA hypomethylation and histone acetylation at the long control region (LCR). Nonetheless, E6/E7 expression was unchanged or decreased in the majority of patients with cervical cancer treated with hydralazine, valproate, or both. In some cervical cancer cell lines, these drugs led to increased transcription of p53, and increased its stabilization due to acetylation at lysines 273 and 282, which allowed a higher bax-protein transactivating effect. CONCLUSION: The results of this study demonstrate that hydralazine and valproate can be safely administered to HPV-related malignancies such as cervical cancer because they do not increase viral oncoprotein expression. Most importantly, the antitumor effect of hydralazine and valproate in cervical cancer may at least partially depend on an up-regulating effect on p53 gene and on the valproate-induced hyperacetylation of p53 protein, protecting it from degradation by E6

Expression of platelet derived growth factor family members and the potential role of imatinib mesylate for cervical cancer

BACKGROUND: Despite significant achievements in the treatment of cervical cancer, it is still a deadly disease; hence newer therapeutical modalities are needed. Preliminary investigations suggest that platelet-derived growth factor (PDGF) might have a role in the development of cervical cancer, therefore it is important to determine whether this growth factor pathway is functional and its targeting with imatinib mesylate leads to growth inhibition of cervical cancer cells. RESULTS: PDGF receptors (PDGFR) and their ligands are frequently expressed in cervical cancer and the majority exhibited a combination of family members co-expression. A number of intronic and exonic variations but no known mutations in the coding sequence of the PDGFRα gene were found in cancer cell lines and primary tumors. Growth assays demonstrated that PDGFBB induces growth stimulation that can be blocked by imatinib and that this tyrosine kinase inhibitor on its own inhibits cell growth. These effects were associated with the phosphorylation status of the receptor. CONCLUSION: The PDGFR system may have a role in the pathogenesis of cervical cancer as their members are frequently expressed in this tumor and cervical cancer lines are growth inhibited by the PDGFR antagonist imatinib

Brachytherapy versus radical hysterectomy after external beam chemoradiation: a non-randomized matched comparison in IB2-IIB cervical cancer patients

<p>Abstract</p> <p>Background</p> <p>A current paradigm in the treatment of cervical cancer with radiation therapy is that intracavitary brachytherapy is an essential component of radical treatment. This is a matched retrospective comparison of the results of treatment in patients treated with external beam chemoradiation (EBRT-CT) and radical hysterectomy versus those treated with identical chemoradiation followed by brachytherapy.</p> <p>Methods</p> <p>In this non-randomized comparison EBRT-CT protocol was the same in both groups of 40 patients. In the standard treated patients, EBRT-CT was followed by one or two intracavitary Cesium (low-dose rate) applications within 2 weeks of finishing external radiation to reach a point A dose of at least 85 Gy. In the surgically treated patients, radical hysterectomy with bilateral pelvic lymph node dissection and para-aortic lymph node sampling were performed within 7 weeks after EBRT-CT. Response, toxicity and survival were evaluated.</p> <p>Results</p> <p>A total of 80 patients were analyzed. The patients receiving EBRT-CT and surgery were matched with the standard treated cases. There were no differences in the clinicopathological characteristics between groups or in the delivery of EBRT-CT. The pattern of acute and late toxicity differed. Standard treated patients had more chronic proctitis while the surgically treated had acute complications of surgery and hydronephrosis. At a maximum follow-up of 60 months, median follow-up 26 (2–31) and 22 (3–27) months for the surgery and standard therapy respectively, eight patients per group have recurred and died. The progression free and overall survival are the same in both groups.</p> <p>Conclusion</p> <p>The results of this study suggest that radical hysterectomy can be used after EBRT-CT without compromising survival in FIGO stage IB2-IIB cervical cancer patients in settings were brachytherapy is not available. A randomized study is needed to uncover the value of surgery after EBRT-CT.</p

A Carboxylesterase 2 Gene Polymorphism as Predictor of Capecitabine on Response and Time to Progression

Este artículo ha sido publicado en la revista Current Drug Metabolism Esta versión tiene Licencia Creative Commons CC-BY-NC-ND Le remito pdf recibido de mi solicitud a la revista del postprint, y que me han enviado por correo electrónico con permiso para su depósito.Capecitabine is a drug that requires the consecutive action of three enzymes: carboxylesterase 2 (CES 2), cytidine deaminase (CDD), and thymidine phosphorylase (TP) for transformation into 5-fluorouracil (5FU). The metabolism of 5FU requires the activity of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) among other enzymes. The present study prospectively examined the possible relationship between the toxicity and efficacy of capecitabine and 14 different polymorphisms in CES 2, CDD, TS and DPD. Between 2003 and 2005, a total of 136 patients with advanced breast or colorectal cancer treated with capecitabine were prospectively enrolled. The presence of two polymorphisms (CDD 943insC and CES 2 Exon3 6046 G/A) were associated with a non-statistically significant higher incidence of grade 3 hand-foot syndrome (HFS) (p=0.07) and grade 3-4 diarrhoea (p=0.09), respectively. Patients heterozygous or homozygous for the polymorphism CES 2 5’UTR 823 C/G exhibited a significantly greater response rate to capecitabine, and time to progression of disease (59%, 8.7 months) than patients with the wild type gene sequence (32%, p=0.015; 5.3 months, p=0.014). For the first time, an association between a polymorphism in the CES2 gene and the efficacy of capecitabine has been described, providing preliminary evidence of its predictive and prognostic value