The Tetrapeptide Acetyl-N-Ser-Asp-Lys-Pro (Goralatide) Protects From Doxorubicin-Induced Toxicity: Improvement in Mice Survival and Protection of Bone Marrow Stem Cells and Progenitors

Abstract

The tetrapeptide Acetyl-N-Ser-Asp-Lys-Pro (AcSDKP or Goralatide), a physiological regulator of hematopoiesis, inhibits the entry into the S-phase of murine and human hematopoietic stem cells. It has been shown to reduce the damage to specific compartments in the bone marrow resulting from treatment with chemotherapeutic agents, ionizing radiations, hyperthermy, or phototherapy. The present study was performed to assess the therapeutic potential of AcSDKP in vivo in reducing both the toxicity and the hematopoietic damage induced by fractionated administration of doxorubicin (DOX), a widely used anticancer drug. Here we showed that AcSDKP could reduce DOX-induced mortality in mice and could protect particularly the long-term reconstituting cells (LTRCs) in addition to colony forming units-spleen, high proliferative potential colony-forming cells, and colony-forming units–granulocyte-macrophage (CFU-GM) from DOX toxicity. The protection against DOX-induced mortality in mice was improved when AcSDKP was administered for 3 days, at a dose of 2.4 μg/d, by continuous subcutaneous (SC) infusion or fractionated SC injections starting 48 hours before DOX treatment. Moreover, the recovery of the CFU-GM population in the AcSDKP-DOX–treated mice was optimized by the subsequent administration of granulocyte colony-stimulating factor (G-CSF). The coadministration of AcSDKP with DOX may improve its therapeutic index by reducing both acute hematotoxicity on late stem cells and progenitors and long-term toxicity on LTRCs. Optimization of these treatments combined with G-CSF may provide an additional approach to facilitate hematopoietic recovery after cancer chemotherapy.

In vivo modifications of AcSDKP metabolism and haematopoiesis in mice treated with 5‐fluorouracil and Goralatide

“…Our results demonstrate partial protection of HPP-CFCs after six injections of 10 mg of Goralatide. Similar protection of haematopoiesis was reported by Aidoudi et al [20], which also used a discontinuous injection protocol, and by Massé et al [21], which used a continuous perfusion device. In addition, we show for the first time that the protective effect of discontinuous injections is not related to a detectable increase in AcSDKP concentrations in BM supernatant.…”

“…Nucleated cells (1 × the proliferation of haematopoietic progenitors and stem cells [26]. This molecule is a potent protector of haematopoiesis because it spares the human and murine progenitors from the in vitro toxicities of 3 0 -azido-3 0 deoxythymidine (AZT) [27], mafosfamide (ASTA Z) [28], phototherapy [29] and hyperthermy [5], and it reduces the in vivo myelotoxicity induced by either anti-cancer drug administration [11,20,21,30] or irradiation [22]. The results of the first human therapeutic trials with Goralatide have shown a slight but significant reduction in the duration and depth of the pancytopenia induced by chemotherapy [12].…”

“…This limited beneficial effect could be due to our insufficient knowledge of the modalities of Goralatide administration required for optimal protection. Using animal models, it has been evidenced recently that the time of initiation and the duration of AcSDKP administration relative to the anticancer treatments are crucial for its myeloprotective effects [20][21][22]. On the other hand, variations of endogenous plasma AcSDKP levels were reported in leukaemic patients treated with chemotherapy, whereas they did not vary in patients with solid tumours [14,15].…”

“…Moreover, we have shown recently that a daily intake of an ACE inhibitor (enalapril) by human healthy volunteers for 15 days significantly increased the plasma concentration and urinary elimination of AcSDKP and modified the levels of circulating haematopoietic progenitors [19]. It has been demonstrated that the dose and time schedules of Goralatide administration are essential for obtaining the maximal bone marrow protection against the toxicity of chemotherapy [20,21] and radiotherapy [22]. Thus, a better knowledge of the in vivo metabolism of endogenous AcSDKP during such treatments could improve the therapeutic use of Goralatide.…”

d‐amino acid modification protects N‐Acetyl‐seryl‐aspartyl‐lysyl‐proline from physiological hydroxylation and increases its antifibrotic effects on hepatic fibrosis

“…N-Acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a ubiquitous molecule that is present in all mammalian tissues and is generated locally from the N-terminal sequence of thymosin β4 by the action of propyl oligopeptidase (3). Originally described as a natural inhibitor of hematopoietic stem cell proliferation, Ac-SDKP is now recognized as a critical negative regulator of fibrosis development in various organs (4)(5)(6). The mechanism of action of Ac-SDKP includes suppression of inflammation, fibroblast proliferation and differentiation, collagen production, and more importantly transforming growth factor-β (TGF-β) signaling (7)(8)(9).…”