Abstract
Objectives:The present study evaluates novel cationic quinoline derivatives known as benzimidazo[3,2-a]quinolinium salts (BQS) named NBQ-48 and ABQ-48 that have structural similarities to known anti-cancer substances such as ellipticine and berberine.Methods:Toledo human lymphoma (ATCC CRL2631) cells were treated for 24 to 48 hours. Apoptosis related endpoints such as cell cycle arrest, mitochondrial damage, RNS and ROS generation and the activity of several apoptosis related proteins such as caspases and apoptosis inducing factor (AIF) were studied using fluorescence staining and western blot respectively.Results:Results indicated a higher toxicity from the amino substituted ABQ-48 versus the NBQ-48 (GI50’s of 50uM versus 100uM respectively). Both compounds induced cell death through various apoptosis related endpoints including a decrease in mitochondrial membrane potential with an increase in ROS and activation of the effector caspase 3. Interestingly, AIF release was observed on cells treated with the amino substituted ABQ-48 but not on the nitro substituted NBQ-48 samples suggesting a caspase independent mechanism for ABQ-48.Conclusions:The results obtained presents the toxic effects of two novel benzimidazo[3,2-a]quinolinium salts in human lymphoma tumor cells. The identified mechanism of action includes multiple apoptosis related effects. Furthermore the data presents a clear variation in caspase dependent or independent mechanism for each compound.
Highlights
Diffuse large B-cell lymphoma is one of the most prevalent Non-Hodgkin’s lymphomas (NHL) in the United States [1]
We present a pair of unnatural alkaloids known as benzimidazo[3,2-a]quinolinium salts (BQS) named 3-nitro- and 3-amino-7 benzylbenzimidazo[3,2-a]quinolinium chlorides (NBQ-48 and ABQ-48, respectively)
Cells were treated with doses ranging from 0μM to 500μM and showed clear differences in dose response effect on cells treated with the two tested compounds
Summary
Diffuse large B-cell lymphoma is one of the most prevalent Non-Hodgkin’s lymphomas (NHL) in the United States [1]. We present a pair of unnatural alkaloids known as benzimidazo[3,2-a]quinolinium salts (BQS) named 3-nitro- and 3-amino-7 benzylbenzimidazo[3,2-a]quinolinium chlorides (NBQ-48 and ABQ-48, respectively) These compounds feature a heteroaromatic planar system which incorporates a quaternized nitrogen Figs. Additional reported activity includes formation of dG – BQS adducts with DNA in an hypoxic environment [7]; this BQS-DNA interaction is similar to what has been reported with ellipticine [8] These previous studies with nitro-substituted BQS (NBQ) have shown possible DNA mediated mechanism of action, the amino-substituted compounds have shown greater toxicity and some activity towards blood cancer as described by the NCI screening panel [9]. In this study we assess the cell death mechanism of action of these novel compounds including apoptosis related endpoints such as cell cycle arrest, mitochondrial damage, caspases activation, RNS and ROS generation and the activity of main apoptosis related proteins
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