Side population (SP) cells mediate chemoresistance in leukemia. However, chemical inhibition approach to target SP cells is poorly studied.

 Herein, we report the discovery of isatin derivatives of nicotinic acid amide as potent side population cell inhibitors.

The selected derivatives showed superior potency over the reference drug Verapamil. Furthermore, the treatment increased chemosensitivity and inhibit the cell proliferation on three different leukemic cell lines, K562, THP-1 and U937, suggested that both SP and the bulk of leukemic cells are affected. Moreover, treatment by most potent compound Nic9 reduced the expression of ABCG2, demonstrated that side population inhibition effect of the target derivatives is at least via ABCG2 inhibition. Importantly, the target derivatives induced erythrocyte/dendritic differentiation to leukemic cells mainly through Musashi/Numb pathway modulation.

To our knowledge, this is the first report to demonstrate functional targeting of leukemic SP cells by using isatin derivatives of nicotinic acid amide, supporting the pre clinical and clinical development to blocks the chemoresistance and induced differentiation to leukemic cells via up regulation of cell fate determined Numb.

Our work represent the modification of vitamins as source of highly effective  and safe drug like compounds for treatement of cancer.

Stem Cell & Tissue Re-Engineering Program, Research Center, King Faisal Specialized Hospital & Research Center, Saudi Arabia is highly acknowledged.