Determining the Anticancer Activity of Sphingosine Kinase Inhibitors Containing Heteroatoms in Their Tail Structure
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 fiv...
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MDPI AG
2022-01-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/1/157 |
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| author | Jitendra Shrestha Seong Woong Kim Su-Bin Kim Yoon Sin Oh Sung Hwan Ki Taeho Lee Sang-Bum Kim Taeuk Park Dong Jae Baek Eun-Young Park |
| author_facet | Jitendra Shrestha Seong Woong Kim Su-Bin Kim Yoon Sin Oh Sung Hwan Ki Taeho Lee Sang-Bum Kim Taeuk Park Dong Jae Baek Eun-Young Park |
| author_sort | Jitendra Shrestha |
| collection | DOAJ |
| description | 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<sub>1–5</sub>). 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 <b>1</b>–<b>20</b> of RB005 and PF-543 derivatives containing an aliphatic chain or a tail structure of benzenesulfonyl were synthesized. All compounds of set 1 (<b>1</b>–<b>10</b>) effectively reduced cell viability in both HT29 and HCT116 cells, whereas set 2 derivatives (<b>11</b>–<b>20</b>) showed poor anticancer effect. Compound <b>10</b>, having the highest cytotoxic effect (48 h, HT29 IC<sub>50</sub> = 6.223 µM, HCT116 IC<sub>50</sub> = 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 <b>10</b> 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 <b>10</b> increased the protein phosphatase 2A (PP2A) activity (1.73 fold) similar to FTY720 (1.65 fold) and RB005 (1.59 fold), whereas compounds <b>11</b> and <b>13</b> 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. |
| first_indexed | 2024-03-10T00:43:07Z |
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| id | doaj.art-60bcec900d5740769d33c0b90280ce25 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T00:43:07Z |
| publishDate | 2022-01-01 |
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| spelling | doaj.art-60bcec900d5740769d33c0b90280ce252023-11-23T15:04:52ZengMDPI AGPharmaceutics1999-49232022-01-0114115710.3390/pharmaceutics14010157Determining the Anticancer Activity of Sphingosine Kinase Inhibitors Containing Heteroatoms in Their Tail StructureJitendra Shrestha0Seong Woong Kim1Su-Bin Kim2Yoon Sin Oh3Sung Hwan Ki4Taeho Lee5Sang-Bum Kim6Taeuk Park7Dong Jae Baek8Eun-Young Park9College of Pharmacy, Mokpo National University, Muan-gun 58554, KoreaCollege of Pharmacy, Mokpo National University, Muan-gun 58554, KoreaCollege of Pharmacy, Mokpo National University, Muan-gun 58554, KoreaDepartment of Food and Nutrition, Eulji University, Seongnam 13135, KoreaCollege of Pharmacy, Chosun University, Gwangju 61452, KoreaCollege of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, KoreaNew Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, KoreaLaboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, KoreaCollege of Pharmacy, Mokpo National University, Muan-gun 58554, KoreaCollege of Pharmacy, Mokpo National University, Muan-gun 58554, KoreaSphingosine 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<sub>1–5</sub>). 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 <b>1</b>–<b>20</b> of RB005 and PF-543 derivatives containing an aliphatic chain or a tail structure of benzenesulfonyl were synthesized. All compounds of set 1 (<b>1</b>–<b>10</b>) effectively reduced cell viability in both HT29 and HCT116 cells, whereas set 2 derivatives (<b>11</b>–<b>20</b>) showed poor anticancer effect. Compound <b>10</b>, having the highest cytotoxic effect (48 h, HT29 IC<sub>50</sub> = 6.223 µM, HCT116 IC<sub>50</sub> = 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 <b>10</b> 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 <b>10</b> increased the protein phosphatase 2A (PP2A) activity (1.73 fold) similar to FTY720 (1.65 fold) and RB005 (1.59 fold), whereas compounds <b>11</b> and <b>13</b> 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.https://www.mdpi.com/1999-4923/14/1/157SK inhibitorcolorectal cancerS1Pderivativeanticancer agentPP2A |
| spellingShingle | Jitendra Shrestha Seong Woong Kim Su-Bin Kim Yoon Sin Oh Sung Hwan Ki Taeho Lee Sang-Bum Kim Taeuk Park Dong Jae Baek Eun-Young Park Determining the Anticancer Activity of Sphingosine Kinase Inhibitors Containing Heteroatoms in Their Tail Structure Pharmaceutics SK inhibitor colorectal cancer S1P derivative anticancer agent PP2A |
| title | Determining the Anticancer Activity of Sphingosine Kinase Inhibitors Containing Heteroatoms in Their Tail Structure |
| title_full | Determining the Anticancer Activity of Sphingosine Kinase Inhibitors Containing Heteroatoms in Their Tail Structure |
| title_fullStr | Determining the Anticancer Activity of Sphingosine Kinase Inhibitors Containing Heteroatoms in Their Tail Structure |
| title_full_unstemmed | Determining the Anticancer Activity of Sphingosine Kinase Inhibitors Containing Heteroatoms in Their Tail Structure |
| title_short | Determining the Anticancer Activity of Sphingosine Kinase Inhibitors Containing Heteroatoms in Their Tail Structure |
| title_sort | determining the anticancer activity of sphingosine kinase inhibitors containing heteroatoms in their tail structure |
| topic | SK inhibitor colorectal cancer S1P derivative anticancer agent PP2A |
| url | https://www.mdpi.com/1999-4923/14/1/157 |
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