Clinical Cancer Drugs - Volume 8, Issue 2, 2021

Background: Colorectal cancer (CRC) is a widespread tumour type amongst men and women. Despite the available screening tests, advanced stage CRC is the most frequent diagnosis. It is treated with cytotoxic chemotherapeutics 5-fluorouracil (5-FU), oxaliplatin (Ox) and irinotecan (CPT-11) that eventually lose their effectiveness as chemoresistance develops. Methods: In this review, the compilation and analysis of PUBMED-retrieved literature data was comprehensively presented and some novel and/or previously poorly described molecular features of CRC unresponsiveness to conventional chemotherapy drugs identified using bioinformatics approach. Complex interactions between previously reported biomarkers of resistance to 5-FU, Ox and CPT-11 were analysed by STRING and cytoHubba accompanied by KEGG pathway enrichment analysis using DAVID functional annotation tool. Results: The bioinformatics analysis has revealed that 5-FU affects ribosome biogenesis and functioning (translational activity), leading to colon cancer cells resistance to 5-FU. Unresponsiveness of CRC to Ox was associated with Rap1 signalling pathway, which opens the possibility of using RAP1A inhibitors as an adjuvant to oxaliplatin in CRC. Furthermore, stem cell markers c-Myc and CD44 as well as Akt kinase emerged as novel resistance biomarkers whose pharmacological targeting could elevate the therapeutic efficacy of irinotecan. Lastly, several pathways common to the resistance to all three drugs were revealed, including miRNAs in cancer, proteoglycans in cancer, cellular senescence and the sphingolipid signalling pathway. Conclusion: This paper gives a comprehensive overview of resistance mechanisms to 5-FU, Ox and irinotecan in colon cancer and reveals several novel molecular players and associated mechanisms that could account for the development of chemoresistance and whose targeting might enable the design of novel combination strategies to overcome resistance to conventional treatment in CRC.

Background: Despite various efforts in preventing and treating SARS-CoV-2 infections; transmission and mortality have been increasing at alarming rates globally. Since its first occurrence in Wuhan, China, in December 2019, the number of cases and deaths due to SARS-CoV- -2 infection continues to increase across 220 countries. Currently, there are about 228 million cases and 4.6 million deaths recorded globally. Although several vaccines/drugs have been reported to prevent or treat SARS-CoV-2, their efficacy to protect against emerging variants and duration of protection are not fully known. Hence, more emphasis is given to repurpose the existing pharmacological agents to manage the infected individuals. One such agent is hydroxychloroquine (HCQ), which is a more soluble derivative of antimalarial drug chloroquine. HCQ has been tested in clinical trials to mitigate SARS-CoV-2 infection-induced complications while reducing the time to clinical recovery (TTCR). However, several concerns and questions about the utility and efficacy of HCQ for treating SARS-CoV-2 infected individuals still persist. Identifying key proteins regulated by HCQ is likely to provide vital clues required to address these concerns. Objective: The objective of this study is to identify the ability of HCQ for binding to the most widely studied molecular targets of SARS-CoV-2 viz., spike glycoprotein (S protein), and main protease (Mpro, also referred as chymotrypsin like protease) using molecular docking approaches and correlate the results with reported mechanisms of actions of HCQ. Methods: X-ray crystallographic structures of spike glycoprotein and main protease of SARSCoV- 2 were retrieved from Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB). The structure of Hydroxychloroquine was retrieved from the PubChem compound database. The binding interactions of the HCQ with target proteins were predicted using CDocker algorithm, and visualized using Discovery studio visualizer. Results: Data from molecular docking studies showed very strong binding of HCQ to the main protease compared to spike glycoprotein. Conclusion: The antiviral activity of HCQ is attributed to its ability to bind to the main protease compared to surface glycoprotein. Therefore, future studies should focus more on developing a combination agent/strategy for targeting surface glycoprotein and main protease together.

Introduction: The established dose of chemotherapy is based on the values of the patient's body weight, where variations during treatment can increase the toxicity of chemotherapy, with the development of nephrotoxicity, among other toxicity profiles, as well as in cases of weight gain, patients may receive low doses and compromise the therapeutic response to the tumor. p>Objective: To evaluate weight gain and loss in cancer patients undergoing chemotherapy. Methods: Longitudinal analytical study with patients at the end of chemotherapy treatment of both genders. The type, location of the tumor and the antineoplastic agent used were collected from the medical records, as well as height and weight at the beginning of treatment. At the time of collection, anthropometric assessment was performed using body mass index, arm circumference, arm muscle circumference, triceps skinfold thickness and percentage of weight loss. Results: Among the patients included in the study, 47.5% had a weight gain of around 2.5 kg, while the remaining patients (52.5%) had a weight loss of around 2.8 kg. Of the patients who had GFR, 55.5% had severe PP, 33.4% had no significant loss and 11.1 had significant loss. In the current study, only 22% had a GFR <60ml/min/1.73m2, but they would already need to readjust the medication calculation. Conclusion: It is important to evaluate body surface variations and also the GFR to adjust the dose of the antineoplastic agent and to prevent or minimize nephrotoxicity, as well as to reduce the risk of underdosing and inefficiency of the therapy.

Background: Chaga mushroom (Inonotus obliquus) is an edible macrofungus used in traditional and folk medicine for the treatment of various gastrointestinal disorders. It has shown potent anti-inflammatory, antioxidant and anticancer effects in several experimental studies, including anti-inflammatory and anticancer effects in colorectal cancer and intestinal inflammation. Whole extract or purified compound ergosterol peroxide from chaga mushroom showed anti-inflammatory mechanism via suppression of NF-ΚB/iNOS-COX-2 and growth inhibitory mechanism via regulation of apoptosis activation and β-catenin suppression. The diverse inflammatory and carcinogenic agents, like carbon tetrachloride (CCl4), a potent hepatotoxic chemical, cause liver damage by inducing lipid peroxidation and other oxidative damages. Aims: The study aimed to analyze the biochemical, cellular and molecular mechanisms of CCl4 induced chronic liver inflammation and carcinoma, and to analyze the effect of the extract of chaga mushroom on liver inflammation and cancer by virtue of anti-inflammatory mechanisms. Method: Physiological, histological and immunohistochemical analyses of the physiological functions and cellular functions were performed. Biochemical assays were conducted for assessing enzymatic changes in tissues. Molecular simulation and docking studies were performed for the evaluation of the molecular interaction. Results: CCl4-exposed mice exhibited a significant decrease in body weight followed by altered histopathological signatures in the liver. Supplementation of IOAE showed that treatment restored the normal structure of the tissues with large round nuclei in most of the cells. CCl4 caused a steep elevation in the levels of SGOT and SGPT to 2.32- and 1.8-fold as compared to control. The LDH level increased to 447 IU/L in CCl4 treated mice as compared to control (236 IU/L). Analysis of the oxidant enzyme pathway showed that CCl4 reduced the GSH level to 16.5 μM as compared to control (52 μM), and induced the catalase enzyme activity up to 259 U/mL as compared to control (124 U/L). These physiological and biochemical alterations were restored towards normal levels by IOAE administration. Immunohistochemical staining for caspase-3 and p53 showed that CCl4 notably increased their expressions, which were subsequently suppressed by administration of IOAE. The molecular simulation and docking studies using ergosterol peroxide from chaga mushroom with iNOS, COX-2 and TNF-α showed binding energy of -10.5, -8.9 and -9.1 Kcal/mol, respectively. These proteins interacting with ergosterol peroxide exerted an inhibitory effect on these critical proinflammatory signaling proteins. Conclusion: The results point out that IOAE is able to prevent damage of hepatic cells caused by CCl4 in mouse models through anti-inflammatory and growth inhibitory mechanisms, which can be utilized for natural prevention of liver toxicity.

Background: As the commonest EGFR-TKI being used in Hong Kong, gefitinib has shown to be efficacious and safe as first-line treatment for L858R mutation and exon 19 deletions with less gastrointestinal and cutaneous adverse events than erlotinib and afatinib. The evidence for therapeutic efficacy for uncommon and complex EGFR mutations, on the other hand, is lacking. It is important to explore whether or not gefitinib is helpful for uncommon and complex EGFR mutations. Objectives: To assess the therapeutic efficacy of gefitinib, as measured by progression-free survival and overall survival, among advanced-stage lung cancer patients with common, uncommon, and complex EGFR mutations. Methods: This retrospective cohort study included 241 Chinese patients with advanced non-smallcell carcinoma of the lung harboring EGFR mutations and received gefitinib 250 mg daily as firstline treatment. The progression-free survival (PFS) and overall survival (OS) for patients with different EGFR mutations, namely exon 19 deletions, L858R mutation in exon 21, uncommon EGFR mutations, and complex EGFR mutations, were analyzed. Results: Among the 241 patients, 118 (49%) had exon 19 deletion, 104 (43%) had L858R mutation in exon 21, 6 (2.5%) had uncommon EGFR mutations, and 13 (5.4%) had complex EGFR mutations. The mean age was 69. 72% of the patients were female, and 81% were non-smokers. Patients with complex EGFR mutations, regardless of the presence of exon 19 deletion and L858R mutation as the component, have better PFS and OS than patients with single common EGFR mutations (Exon 19 deletion or L858R mutation). Patients with uncommon EGFR mutations have inferior PFS and OS than those with common EGFR mutations. Conclusion: Gefitinib is a possible option for patients with complex EGFR mutations, while it may not be the preferred treatment option in patients with single uncommon EGFR mutations.

Background: Pateints with acute leukemia along with febrile neutropenia is at risk for fungal as well as bacterial infections. Fungal infection is a more serious and common infection in this setting, leading to a high mortality rate. There is limited data on clinical factors predictive of fungal infection in acute leukemia with febrile neutropenia. Objective: This study aimed to evaluate clinical predictive factors of fungal infection in acute leukemia patients with FN. Methods: This was a retrospective analytical study and included adult patients diagnosed with acute leukemia, who developed FN, and had positive culture with either bacterial or fungal infection. Predictors for fungal infection were calculated by using logistic regression analysis. A subgroup analysis in patients with acute myeloid leukemia (AML) was also performed. Results: There were 94 patients who met the study criteria. Of those, 29 patients had positive culture for fungus (30.82%), categorized as Aspergillus (19 patients; 65.51%) and Candida (10 patients; 34.49%). The mortality rate was significantly higher in the fungal infection group than the bacterial infection group (24.14% vs. 6.15%; p 0.031). There were six factors in the final model predictive of fungal infection with one independent predictor: treatment regimen of Idarubicin plus Ara-C with an adjusted odds ratio of 5.188 (95% CI of 1.386, 19.419). A subgroup analysis for fungal infection in patients with AML showed that only the treatment regimen of Idarubicin plus Ara- C was a significant factor. Its adjusted odds ratio was 5.138 (95% CI of 1.156, 24.467). Conclusion: Treatment with idarubicin and Ara-C may increase the risk of fungal infection in acute leukemia patients with FN.