Eunus S. Ali's research while affiliated with Flinders University and other places

The transient receptor potential melastatin subfamily member 2 (TRPM2), a thermo and reactive oxygen species (ROS) sensitive Ca ²⁺ -permeable cation channel has a vital role in surviving the cell as well as defending the adaptability of various cell groups during and after oxidative stress. It shows higher expression in several cancers involving breast, pancreatic, prostate, melanoma, leukemia, and neuroblastoma, indicating it raises the survivability of cancerous cells. In various cancers including gastric cancers, and neuroblastoma, TRPM2 is known to conserve viability, and several underlying mechanisms of action have been proposed. Transcription factors are thought to activate TRPM2 channels, which is essential for cell proliferation and survival. In normal physiological conditions with an optimal expression of TRPM2, mitochondrial ROS is produced in optimal amounts while regulation of antioxidant expression is carried on. Depletion of TRPM2 overexpression or activity has been shown to improve ischemia–reperfusion injury in organ levels, reduce tumor growth and/or viability of various malignant cancers like breast, gastric, pancreatic, prostate, head and neck cancers, melanoma, neuroblastoma, T-cell and acute myelogenous leukemia. This updated and comprehensive review also analyzes the mechanisms by which TRPM2-mediated Ca ²⁺ signaling can regulate the growth and survival of different types of cancer cells. Based on the discussion of the available data, it can be concluded that TRPM2 may be a unique therapeutic target in the treatment of several types of cancer.

Glioblastoma (GBM) remains one of the most resistant and fatal forms of cancer. Previous studies have examined primary and recurrent GBM tumors, but it is difficult to study tumor evolution during therapy where resistance develops. To investigate this, we performed an in vivo single-cell RNA sequencing screen in a patient-derived xenograft (PDX) model. Primary GBM was modeled by mice treated with DMSO control, recurrent GBM was modeled by mice treated with temozolomide (TMZ), and during therapy GBM was modeled by mice euthanized after two of five TMZ treatments. Our analysis revealed the cellular population present during therapy to be distinct from primary and recurrent GBM. We found the Ribonucleotide Reductase gene family to exhibit a unique signature in our data due to an observed subunit switch to favor RRM2 during therapy. GBM cells were shown to rely on RRM2 during therapy causing RRM2-knockdown (KD) cells to be TMZ-sensitive. Using targeted metabolomics, we found RRM2-KDs to produce less dGTP and dCTP than control cells in response to TMZ (p<0.0001). Supplementing RRM2-KDs with deoxycytidine and deoxyguanosine rescued TMZ-sensitivity, suggesting an RRM2-driven mechanism of chemoresistance, established by regulating the production of these nucleotides. In vivo, tumor-bearing mice treated with the RRM2-inhibitor, Triapine, in combination with TMZ, survived longer than mice treated with TMZ alone (p<0.01), indicating promising clinical opportunities in targeting RRM2. Our data present a novel understanding of RRM2 activity, and its alteration during therapeutic stress as response to TMZ-induced DNA damage.

The PI3K-Akt-mechanistic (formerly mammalian) target of the rapamycin (mTOR) signaling pathway is important in a variety of biological activities, including cellular proliferation, survival, metabolism, autophagy, and immunity. Abnormal PI3K-Akt-mTOR signalling activation can promote transformation by creating a cellular environment conducive to it. Deregulation of such a system in terms of genetic mutations and amplification has been related to several human cancers. Consequently, mTOR has been recognized as a key target for the treatment of cancer, especially for treating cancers with elevated mTOR signaling due to genetic or metabolic disorders. In vitro and in vivo, rapamycin which is an immunosuppressant agent actively suppresses the activity of mTOR and reduces cancer cell growth. As a result, various sirolimus-derived compounds have now been established as therapies for cancer, and now these medications are being investigated in clinical studies. In this updated review, we discuss the usage of sirolimus-derived compounds and other drugs in several preclinical or clinical studies as well as explain some of the challenges involved in targeting mTOR for treating various human cancers.

MAPK (mitogen-activated protein kinase) or ERK (extracellular-signal-regulated kinase) pathway is an important link in the transition from extracellular signals to intracellular responses. Because of genetic and epigenetic changes, signal-ing cascades are altered in a variety of diseases, including cancer. Extant studies on the homeostatic and pathologic behavior of MAPK signaling have been conducted; however, much remains to be explored in preclinical and clinical research in terms of regulation and action models. MAPK has implications for cancer therapy response, more specifically in response to experimental MAPK suppression, compensatory mechanisms are activated. The current study investigates MAPK as a very complex cell signaling pathway that plays roles in cancer treatment response, cellular normal conduit maintenance, and compensatory pathway activation. Most MAPK inhibitors, unfortunately, cause resistance by activating compensatory feedback loops in tumor cells and tumor microenvironment components. As a result, innovative combinatorial treatments for cancer management must be applied to limit the likelihood of alternate pathway initiation as a possibility for generating novel therapeutics based on incorporation in translational research. We summarize current knowledge about the implications of ERK (MAPK) in cancer, as well as bioactive products from plants, microbial organisms or marine organisms, as well as the correlation with their chemical structures, which modulate this pathway for the treatment of different types of cancer.

This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Proffered Abstracts section (PR011) of the Conference Proceedings. Citation Format: Atique U. Ahmed, Jack M. Shireman, Fatemeh Atash, Gina Lee, Eunus S. Ali, Miranda R. Saathoff, Cheol H. Park, Sol Savchuk, Shivani Baisiwala, Jason Miska, Maciej S. Lesniak, C. David James, Roger Stupp, Priya Kumthekar, Craig M. Horbinski, Issam Ben-Sahra. Targeting cellular plasticity-driven metabolic adaptation to overcome chemoresistance in GBM [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B034.

A new bioactive naphthalene glucoside, named neanoside C (1), was isolated from the aerial part of Neanotis wightiana. The structure of neanoside C (1) was elucidated as 1,4-dihydroxy-2-(6′-Omethylglucopyranosyloxymethyl)-naphthalene-3-vinyloxyglucopyranoside by interpretation of the spectroscopic data, including 2D NMR and chemical studies. Neanoside C (1) was further subjected to screening for anticancer potential using MTT based cytotoxicity assay, LDH leakage assay, and estimation of intracellular ROS production in two human breast cancer cell line. The compound exhibited promising anti-proliferative and cytotoxic effect against MCF-7 and MDA-MB-231 cell lines with an IC50 value of 22.77 nM and 35.71 nM, respectively. Neanoside C (1) also exhibited concentration-dependent intracellular LDH leakage and ROS production.

This year nearly 20,000 lives will be lost to Glioblastoma (GBM), a treatment-resistant primary brain cancer. In this study, we identified a molecular circuit driven by epigenetic regulation that regulates the expression of ciliary protein ALR13B. We also demonstrated that ARL13B subsequently interacts with purine biosynthetic enzyme IMPDH2. Removal of ARL13B enhanced TMZ-induced DNA damage by reducing de-novo purine biosynthesis and forcing GBM cells to rely on the purine salvage pathway. Furthermore, targeting can be achieved by using an FDA-approved drug, Mycophenolate Moefitil. Our results suggest a clinical evaluation of MMF in combination with TMZ treatment in glioma patients.

Nerol, a monoterpene is evident to possess diverse biological activities, including antioxidant, anti-microbial, anti-spasmodic, anthelmintic, and anti-arrhythmias. This study aims to evaluate its hepatoprotective effect against paracetamol-induced liver toxicity in a rat model. Five groups of rats (n =7) were orally treated (once daily) with 0.05% tween 80 dissolved in 0.9% NaCl solution (vehicle), paracetamol 640 mg/kg (negative con trol), 50 mg/kg silymarin (positive control), or nerol (50 and 100 mg/kg) for 14 days, followed by the toxicity induction using paracetamol (PCM). The blood samples and livers of the animals were collected and subjected to biochemical and microscopical analysis. The histological findings suggest that paracetamol caused lymphocyte infiltration and marked necrosis, whereas maintenance of the normal hepatic structural was observed in group pre-treated with silymarin and nerol. The rats pre-treated with nerol significantly and dose- dependently reduced the hepatotoxic markers in animals. Nerol at 100 mg/kg significantly reversed the paracetamol-induced altered situations, including the liver enzymes, plasma proteins, antioxidant enzymes and serum bilirubin, lipid peroxidation (LPO) and cholesterol [e.g., total cholesterol (TC), triglycerides (TG), high- density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c)] levels in animals. Taken together, nerol exerted significant hepatoprotective activity in rats in a dose-dependent manner. PCM-induced toxicity and nerol induced hepatoprotective effects based on expression of inflammatory and apoptosis factors will be future line of work for establishing the precise mechanism of action of nerol in Wistar albino rats.

These authors contributed equally to this work. Glioblastoma is a primary brain cancer with a near 100% recurrence rate. Upon recurrence, the tumour is resistant to all conventional therapies, and because of this, 5-year survival is dismal. One of the major drivers of this high recurrence rate is the ability of glioblastoma cells to adapt to complex changes within the tumour microenvironment. To elucidate this adaptation's molecular mechanisms, specifically during temozolomide chemotherapy, we used chromatin immunoprecipitation followed by sequencing and gene expression analysis. We identified a molecular circuit in which the expression of ciliary protein ADP-ribosylation factor-like protein 13B (ARL13B) is epigenetically regulated to promote adaptation to chemotherapy. Immuno-precipitation combined with liquid chromatography-mass spectrometry binding partner analysis revealed that that ARL13B interacts with the purine biosynthetic enzyme inosine-5 0-monophosphate dehydrogenase 2 (IMPDH2). Further, radioisotope tracing revealed that this interaction functions as a negative regulator for purine salvaging. Inhibition of the ARL13B-IMPDH2 interaction enhances temozolomide-induced DNA damage by forcing glioblastoma cells to rely on the purine salvage pathway. Targeting the ARLI3B-IMPDH2 circuit can be achieved using the Food and Drug Administration-approved drug, mycophenolate mofetil, which can block IMPDH2 activity and enhance the therapeutic efficacy of temozolomide. Our results suggest and support clinical evaluation of MMF in combination with temozolomide treatment in glioma patients.