A- Investigation of anticancer and multidrug resistance (MDR) reversal agents and their mechanisms of action by application of cell biology techniques

Cancer is a leading cause of death worldwide. There is always a great need for new anticancer drugs with better efficacy and fewer adverse effects.

Compounds with various structures are tested in our drug discovery programs. Small molecules synthesized by us or our collaborators in Iran, Italy, Portugal, India, Spain, etc as well as natural products isolated from plant extracts are tested with the aim of finding new agents with therapeutic potential in cancer. Our cancer research is divided in two main categories:A-


۱ Discovery of small-molecule anticancer agents from synthetic or natural sources:Different

cancer cell lines including colon, breast, lung, leukemia, lymphoma, etc, are used for screening of cytotoxic activity. Interesting compounds are then further assessed for their mechanisms of action including cell cycle alterations (by flow cytometry), apoptosis induction (by flow cytometry), caspase-۳ activation (by western blot), intracellular reactive oxygen species (ROS) production (by fluorimetry), etc.


A-۲ Multidrug resistance (MDR) reversal agents:MDR

, which is the resistance of cancer cells to several unrelated chemotherapeutic drugs, is an important obstacle for management of several types of cancer.

We use cell models such as MES-SA-DX۵ (a model of typical MDR, overexpressing P-gp) and HL۶۰-MX۱ (a model of atypical MDR, overexpressing topoisomerase II) and their non-MDR parental cells (MES-SA and HL-۶۰, respectively) for assessment of MDR reversal capacity of different small molecules. Alterations of resistance to standard anticancer agents such as doxorubicin and mitoxanterone (by MTT assay), rhodamine efflux (by flow cytometry), P-gp expression (by western blot) are studied as indices of MDR.


B- Using neuronal cell models to study the therapeutic action of small molecules in neurodegenerative diseases

Alzheimer disease and other age-related neurodegenerative disorders are devastating pathologies that have become huge health problems with the constant growth of the old age population. In our drug discovery programs, small molecules synthesized by us or our collaborators as well as products isolated from natural sources are tested with the aim of finding new therapeutic agents for neurodegenerative diseases. These efforts are divided in the following categories:B-


۱- β-secretase (BACE-۱) inhibitors:Enzymatic
assays as well as cells over-expressing amyloid precursor protein (APP) are used.


B-۲- Small molecule neurotrophin mimetics:Compounds

capable of agonistic action on tropomysoin receptor kinase (Trk) receptors that mimic the action of neurotrophins such as nerve growth factor (NGF) are tested.


B-۳- Inhibitors of oxidative stress-induced apoptosis in neuronal cells:Inhibitors
of apoptosis induced by H۲O۲ and Amyloid-beta in neuronal cell lines such as PC۱۲ and SH-SY۵Y are tested.