Abstract
Advanced stage cancers are aggressive and difficult to treat with mono-therapeutics, substantially decreasing patient survival rates. Hence, there is an urgent need to develop unique therapeutic approaches to treat cancer with superior potency and efficacy. This study investigates a new approach to develop a potent combinational therapy to treat advanced stage leukemia. Biologically active α-amino amide analogs (RS)-N-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)-N-phenylpropiolamide (α-AAA-A) and (RS)-N-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)-N-phenylbut2-enamide (α-AAA-B) were synthesized using linear Ugi multicomponent reaction. Cytotoxicities and IC50 values of α-AAA-A and α-AAA-B against leukemia cancer cell lines (HL-60 and K562) were analyzed though MTT assay. Cytotoxic assay analyzed percent killing of leukemia cell lines due to the effect of γδ T cells alone or in combination with α-AAA-A or α-AAA-B. Synthesized biologically active molecule α-AAA-A exhibited increased cytotoxicity of HL-60 (54%) and K562 (44%) compared with α-AAA-B (44% and 36% respectively). Similarly, α-AAA-A showed low IC50 values for HL-60 (1.61 ± 0.11 μM) and K562 (3.01 ± 0.14 μM) compared to α-AAA-B (3.12 ± 0.15 μM and 6.21 ± 0.17 μM respectively). Additive effect of amide analogs and γδ T cells showed significantly high leukemia cancer cell killing as compared to γδ T cells alone. A unique combinational therapy with γδ T cells and biologically active anti-cancer molecules (α-AAA-A/B), concomitantly may be a promising cancer therapy.
Highlights
Cancer is a disease characterized by uncontrolled growth of cells, causing mortality worldwide
Most of the drugs used in the treatment of leukemia cause severe toxicities and, it is important to synthesize and test novel biologically active molecules which can potentially be used as anti-cancer agents with low toxicities
The cytotoxic effects of both biologically active molecules were analyzed for two different leukemia cancer cell lines (HL-60 and K562)
Summary
Cancer is a disease characterized by uncontrolled growth of cells, causing mortality worldwide. In 2018, it was estimated that cancer was the second leading cause of death worldwide and was responsible for 9.6 million deaths [1]. A substantial number of cancer related deaths in the Saudi adult population were due to colorectal cancer (males; 19.3%) and breast cancer (females; 29%) [World Health OrganizationCancer Country Profiles, [3]]. According to statistics reported in 2018, the most common type of cancer among Saudi children of both sexes was leukemia (34.6%) [4]. Severe toxicities (cardiotoxicity, neuropathy, hepatotoxicity, renal toxicity etc.) have been registered for almost all the drugs, which may cause morbidity and mortality in patients [5,6,7,8]. Best approach to reduce the burden of these toxicities is to strategize for better outcome for patients
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