DZ-BAU2021-14N AS NOVEL PYRAZOLOPYRIDINE NANOCRYSTALS: APPRAISAL OF ANTICANCER ACTIVITY AGAINST HCT-116 AND HT-29 COLORECTAL CANCER CELL LINES

Mentioning DZ-BAU2021-14 (C19H17N5O2,347.370 g/mol) developed in BAU Labs, its promising preliminary antitumor effect nominated it to be selected as a lead antiproliferative compound against colorectal cancer cell lines owing to its proved Cyclin Dependent Kinase 2 (CDK2) inhibition (Kassem et al., 2021). Solving many problems restricting traditional cancer therapy, nanotechnology is offering safety margins and targeted delivery of poorly soluble drug. The potential effect of this compound was combined with the advantages of nanotechnology, precisely nanocrystals to achieve better antiproliferative and hopeful less cytotoxic patterns. The nanocrystals DZ-BAU2021-14N were prepared by an antisolvent precipitation technique using Poloxamer 407 and Cremophor® RH 40 as stabilizers. The nanocrystals were obtained with a nanometric particle size (89.80 ± 11.2 nm) and a negative zeta potential (-32.6 ± 0.50 mV) and were stable at 4 ± 0.5°C with no significant change in particle size or zeta potential. The anticancer activity of DZ-BAU2021-14 and DZ-BAU2021-14N were assessed. Their antiproliferative effects against colorectal cancer cell lines HCT-116 and HT-29 were studied via viability assay. In addition, their cytotoxic effects on non-tumorigenic cell lines NCM-460D were evaluated and respective IC50 values were determined. Different responses were obtained; DZ-BAU2021-14N provided lower IC50 on HCT-116 compared to the free drug DZ-BAU2021-14 (27 and 22 µM, respectively). The safety profile of the free drug was reflected by its IC50 on NCM-460D of 200µM while that of drug nanocrystals showed relative cytotoxicity with IC50 of 33µM, and this requires further investigation to study this response

Novel therapeutic strategies for spinal osteosarcomas

At the dawn of the third millennium, cancer has become the bane of twenty-first century man, and remains a predominant public health burden, affecting welfare and life expectancy globally. Spinal osteogenic sarcoma, a primary spinal malignant tumor, is a rare and challenging neoplastic disease to treat. After the conventional therapeutic modalities of chemotherapy, radiation and surgery have been exhausted, there is currently no available alternative therapy in managing cases of spinal osteosarcoma. The defining signatures of tumor survival are characterised by cancer cell ability to stonewall immunogenic attrition and apoptosis by various means. Some of these biomarkers, namely immune-checkpoints, have recently been exploited as druggable targets in osteosarcoma and many other different cancers. These promising strides made by the use of reinvigorated immunotherapeutic approaches may lead to significant reduction in spinal osteosarcoma disease burden and corresponding reciprocity in increase of survival rates. In this review, we provide the background to spinal osteosarcoma, and proceed to elaborate on contribution of the complex ecology within tumor microenvironment giving arise to cancerous immune escape, which is currently receiving considerable attention. We follow this section on the tumor microenvironment by a brief history of cancer immunity. Also, we draw on the current knowledge of treatment gained from incidences of osteosarcoma at other locations of the skeleton (long bones of the extremities in close proximity to the metaphyseal growth plates) to make a case for application of immunity-based tools, such as immune-checkpoint inhibitors and vaccines, and draw attention to adverse upshots of immune-checkpoint blockers as well. Finally, we describe the novel biotechnique of CRISPR/Cas9 that will assist in treatment approaches for personalized medication.This work is funded by a grant (MPP 320133) from the American University of Beirut to Dr. Ali H. Eid

A Journey Under the Sea: The Quest for Marine Anti-Cancer Alkaloids

The alarming increase in the global cancer death toll has fueled the quest for new effective anti-tumor drugs thorough biological screening of both terrestrial and marine organisms. Several plant-derived alkaloids are leading drugs in the treatment of different types of cancer and many are now being tested in various phases of clinical trials. Recently, marine-derived alkaloids, isolated from aquatic fungi, cyanobacteria, sponges, algae, and tunicates, have been found to also exhibit various anti-cancer activities including anti-angiogenic, anti-proliferative, inhibition of topoisomerase activities and tubulin polymerization, and induction of apoptosis and cytotoxicity. Two tunicate-derived alkaloids, aplidin and trabectedin, offer promising drug profiles, and are currently in phase II clinical trials against several solid and hematologic tumors. This review sheds light on the rich array of anti-cancer alkaloids in the marine ecosystem and introduces the most investigated compounds and their mechanisms of action

Retinoids and Reactive Oxygen Species in Cancer Cell Death and Therapeutics

Retinoids are a large family of structurally related natural and synthetic molecules that exhibit a variety of effects in embryogenesis and adult life. The parent compound of retinoids is vitamin A which was first discovered for its impact on vision and later on cell proliferation, cell differentiation, and cell death. Clinically, retinoids were used for six decades in cancer management as they exhibit antitumor effects such as inhibiting cellular proliferation, inducing apoptosis, modulating cell cycle, and cell differentiation. Initially, early research focused on the mechanism of action of retinoids by their binding to retinoic acid receptors. However, recently accumulated evidence points that retinoids can act independent of the retinoid receptor signaling pathway for example by inducing stress, changes in redox balance, and reactive oxygen species (ROS) generation, and modulation of pathways that do not require binding of transcription factors to retinoic acid responsive DNA sequences. This review focuses on the mechanism of action of natural as well as synthetic retinoids, in particular, on the generation of ROS in in vitro and in vivo tumor models. A better understanding of the effects of retinoids on cellular redox balance and oxidative stress will impact future strategies of cancer management and therapy.Scopu

Differential Growth Inhibitory Effects of Highly Oxygenated Guaianolides Isolated from the Middle Eastern Indigenous Plant Achillea falcata in HCT-116 Colorectal Cancer Cells

Medicinal plants play a crucial role in traditional medicine and in the maintenance of human health worldwide. Sesquiterpene lactones represent an interesting group of plant-derived compounds that are currently being tested as lead drugs in cancer clinical trials. Achillea falcata is a medicinal plant indigenous to the Middle Eastern region and belongs to the Asteraceae family, which is known to be rich in sesquiterpene lactones. We subjected Achillea falcata extracts to bioassay-guided fractionation against the growth of HCT-116 colorectal cancer cells and identified four secotanapartholides, namely 3-β-methoxy- isosecotanapartholide (1), isosecotanapartholide (2), tanaphallin (3), and 8-hydroxy-3-methoxyisosecotanapartholide (4). Three highly oxygenated guaianolides were isolated for the first time from Achillea falcata, namely rupin A (5), chrysartemin B (6), and 1β, 2β-epoxy- 3β,4α,10α-trihydroxyguaian- 6α,12-olide (7). These sesquiterpene lactones showed no or minor cytotoxicity while exhibiting promising anticancer effects against HCT-116 cells. Further structure-activity relationship studies related the bioactivity of the tested compounds to their skeleton, their lipophilicity, and to the type of functional groups neighboring the main alkylating center of the molecule

The Effect of Different Ester Chain Modifications of Two Guaianolides for Inhibition of Colorectal Cancer Cell Growth

Several sesquiterpene lactones (STLs) have been tested as lead drugs in cancer clinical trials. Salograviolide-A (Sal-A) and salograviolide-B (Sal-B) are two STLs that have been isolated from Centaurea ainetensis, an indigenous medicinal plant of the Middle Eastern region. The parent compounds Sal-A and Sal-B were modified and successfully prepared into eight novel guaianolide-type STLs (compounds 1–8) bearing ester groups of different geometries. Sal-A, Sal-B, and compounds 1–8 were tested against a human colorectal cancer cell line model with differing p53 status; HCT116 with wild-type p53 and HCT116 p53−/− null for p53, and the normal-like human colon mucosa cells with wild-type p53, NCM460. IC50 values indicated that derivatization of Sal-A and Sal-B resulted in potentiation of HCT116 cell growth inhibition by 97% and 66%, respectively. The effects of the different molecules on cancer cell growth were independent of p53 status. Interestingly, the derivatization of Sal-A and Sal-B molecules enhanced their anti-growth properties versus 5-Fluorouracil (5-FU), which is the drug of choice in colorectal cancer. Structure-activity analysis revealed that the enhanced molecule potencies were mainly attributed to the position and number of the hydroxy groups, the lipophilicity, and the superiority of ester groups over hydroxy substituents in terms of their branching and chain lengths. The favorable cytotoxicity and selectivity of the potent molecules, to cancer cells versus their normal counterparts, pointed them out as promising leads for anti-cancer drug design