Retracted: Antitumor effects of OSU‐2S, a nonimmunosuppressive analogue of FTY720, in hepatocellular carcinoma

Abstract

Accumulating evidence suggests the therapeutic potential of the immunosuppressive agent FTY720 (fingolimod) in hepatocellular carcinoma (HCC). Based on our previous finding that FTY720 mediates apoptosis in HCC cells by activating reactive oxygen species (ROS)-protein kinase (PK)Cδ signaling independent of effects on sphingosine-1-phosphate (S1P) receptors, we embarked on the pharmacological exploitation of FTY720 to develop a non-immunosuppressive analogue with antitumor activity. This effort led to the development of OSU-2S, which exhibits higher potency than FTY720 in suppressing HCC cell growth through PKCδ activation. In contrast to FTY720, OSU-2S was not phosphorylated by sphingosine kinase (SphK)2 in vitro, and did not cause S1P1 receptor internalization in HCC cells or T lymphocyte homing in immunocompetent mice. Though devoid of S1P1 receptor activity, OSU-2S exhibited higher in vitro antiproliferative efficacy relative to FTY720 against HCC cells without cytotoxicity in normal hepatocytes. Several lines of pharmacological and molecular genetic evidence indicate that ROS-PKCδ-caspase-3 signaling underlies OSU-2S-mediated antitumor effects, and that differences in the antitumor activity between FTY720 and OSU-2S were attributable to SphK2-mediated phosphorylation of FTY720, which represents a metabolic inactivation of its antitumor activity. Finally, OSU-2S exhibited high in vivo potency in suppressing xenograft tumor growth in both ectopic and orthotopic models without overt toxicity. Conclusion: Using the molecular platform of FTY720, we developed OSU-2S, a novel PKCδ-targeted antitumor agent, which is devoid of S1P1 receptor activity and is highly effective in suppressing HCC tumor growth in vivo. These findings suggest that OSU-2S has clinical value in therapeutic strategies for HCC and warrants continued investigation in this regard.

Lyn sustains oncogenic signaling in chronic lymphocytic leukemia by strengthening SET-mediated inhibition of PP2A

“…These data are in line with recent evidence showing that nonphosphorylatable FTY720 analogs unleash apoptosis in a number of cancers by such a mechanism. 44,46,51,56 Moreover, the use of MP07-66 in combination with dasatinib results in the amplification of CLL apoptosis in a synergistic manner, supporting our hypothesis that 2 different inhibitory events (ie, tyrosine phosphorylation and interaction with SET) converge onto a single target, PP2A, and closely cooperate in generating a vicious circle that maintains the survival of CLL. Of note, this is in agreement with other studies regarding other types of leukemia, including acute myeloid leukemia and chronic myeloid leukemia, where the synergistic action of tyrosine kinase inhibitors and SET antagonists in inducing apoptosis has been observed, and a combination of these agents has been proposed as a therapeutic approach for patients with disease persistence or tyrosine kinase inhibitor resistance.…”

“…To circumvent this issue, other authors have developed FTY720 analogs with potent cytotoxicity against specific neoplasms, devoid of sphingosine-1-phosphate receptor-mediated immunosuppressive effects and shown to activate PP2A, thereby unleashing the apoptotic cascades. 45,46 Considering these promising findings and the findings herein reported on PP2A in CLL, we designed a number of FTY720 analogs to be tested for their ability to exert antitumor activity by activating PP2A, but insusceptible to sphingosine kinase 2 (SK-2) phosphorylation and hence unable to cause S1P1 internalization. 47,48 Figure 6A shows 4 of the 10 FTY720 analogs, which were designed taking into account the structural properties of FTY720 that mediate its effects and were properly modified on the basis of the functional results achieved.…”

FTY720 for cancer therapy (Review)

“…However, whether FTY720 induces apoptosis or cell death depends on cell types. Of note, OSU-2S, a non-immunosuppressive analogue of FTY720, increased ROS generation, suppressed cell growth in the same way as FTY720 in hepatocellular carcinoma (40), suggesting a direct effect on ROS of unphosphorylated form of FTY720.…”

PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells

“…FTY720 was synthesized with subsequent HPLC purification (47), and identity/purity was confirmed by nuclear magnetic resonance and mass spectrometry. (S)-FTY720-OMe, OSU-2S, and (S)-FTY720-regioisomer were synthesized as described previously (48,49).…”