Determining the Anticancer Activity of Sphingosine Kinase Inhibitors Containing Heteroatoms in Their Tail Structure

• Published in: Pharmaceutics 2022-01, Vol.14 (1), p.157
• Main Authors: Shrestha, Jitendra, Kim, Seong Woong, Kim, Su-Bin, Oh, Yoon Sin, Ki, Sung Hwan, Lee, Taeho, Kim, Sang-Bum, Park, Taeuk, Baek, Dong Jae, Park, Eun-Young
• Format: Article
• Language: English
• Subjects: Angiogenesis; anticancer agent; Cancer; Cell growth; Chromatography; colorectal cancer; derivative; Kinases; Phenols; PP2A; S1P; SK inhibitor
• ISSN: 1999-4923; 1999-4923
• DOI: 10.3390/pharmaceutics14010157

Sphingosine kinase (SK) enzyme, a central player of sphingolipid rheostat, catalyzes the phosphorylation of sphingosine to the bioactive lipid mediator sphingosine 1 phosphate (S1P), which regulates cancer cell proliferation, migration, differentiation, and angiogenesis through its extracellular five G protein-coupled S1P receptors (S1PR ). Recently, several research studies on SK inhibitors have taken place in order use them for the development of novel anticancer-targeted therapy. In this study, we designed and synthesized analog derivatives of known SK1 inhibitors, namely RB005 and PF-543, by introducing heteroatoms at their tail structure, as well as investigated their anticancer activities and pharmacokinetic parameters in vitro. Compounds - of RB005 and PF-543 derivatives containing an aliphatic chain or a tail structure of benzenesulfonyl were synthesized. All compounds of set 1 ( - ) effectively reduced cell viability in both HT29 and HCT116 cells, whereas set 2 derivatives ( - ) showed poor anticancer effect. Compound , having the highest cytotoxic effect (48 h, HT29 IC = 6.223 µM, HCT116 IC = 8.694 µM), induced HT29 and HCT116 cell death in a concentration-dependent manner through the mitochondrial apoptotic pathway, which was demonstrated by increased annexin V-FITC level, and increased apoptotic marker cleaved caspase-3 and cleaved PARP. Compound inhibited SK1 by 20%, and, thus, the S1P level decreased by 42%. Unlike the apoptosis efficacy, the SK1 inhibitory effect and selectivity of the PF-543 derivative were superior to that of the RB005 analog. As a result, compounds with an aliphatic chain tail exhibited stronger apoptotic effects. However, this ability was not proportional to the degree of SK inhibition. Compound increased the protein phosphatase 2A (PP2A) activity (1.73 fold) similar to FTY720 (1.65 fold) and RB005 (1.59 fold), whereas compounds and had no effect on PP2A activation. Since the PP2A activity increased in compounds with an aliphatic chain tail, it can be suggested that PP2A activation has an important effect on anticancer and SK inhibitory activities.