Combating Acute Myeloid Leukemia via Sphingosine Kinase 1 Inhibitor-Nanomedicine Combination Therapy with Cytarabine or Venetoclax

Thao M Nguyen; Paul Joyce; David M Ross; Kristen Bremmell; Manasi Jambhrunkar; Sook S Wong; Clive A Prestidge

doi:10.3390/pharmaceutics16020209

Combating Acute Myeloid Leukemia via Sphingosine Kinase 1 Inhibitor-Nanomedicine Combination Therapy with Cytarabine or Venetoclax

Pharmaceutics. 2024 Jan 31;16(2):209. doi: 10.3390/pharmaceutics16020209.

Authors

Thao M Nguyen^{1

2}, Paul Joyce¹, David M Ross^{2

3

4

5}, Kristen Bremmell¹, Manasi Jambhrunkar¹, Sook S Wong¹, Clive A Prestidge¹

Affiliations

¹ Centre for Pharmaceutical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA 5001, Australia.
² Adelaide Medical School, University of Adelaide, Adelaide, SA 5001, Australia.
³ Department of Haematology, Flinders University and Medical Centre, Adelaide, SA 5001, Australia.
⁴ Department of Haematology and Bone Marrow Transplantation, Royal Adelaide Hospital, Adelaide, SA 5001, Australia.
⁵ Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5001, Australia.

Abstract

MP-A08 is a novel sphingosine kinase 1 (SPHK1) inhibitor with activity against acute myeloid leukemia (AML). A rationally designed liposome-based encapsulation and delivery system has been shown to overcome the physicochemical challenges of MP-A08 and enable its effective delivery for improved efficacy and survival of mice engrafted with human AML in preclinical models. To establish therapies that overcome AML's heterogeneous nature, here we explored the combination of MP-A08-loaded liposomes with both the standard chemotherapy, cytarabine, and the targeted therapy, venetoclax, against human AML cell lines. Cytarabine (over the dose range of 0.1-0.5 µM) in combination with MP-A08 liposomes showed significant synergistic effects (as confirmed by the Chou-Talalay Combination Index) against the chemosensitised human AML cell lines MV4-11 and OCI-AML3. Venetoclax (over the dose range of 0.5-250 nM) in combination with MP-A08 liposomes showed significant synergistic effects against the chemosensitised human AML cell lines, particularly in venetoclax-resistant human AML cells. This strong synergistic effect is due to multiple mechanisms of action, i.e., inhibiting MCL-1 through SPHK1 inhibition, leading to ceramide accumulation, activation of protein kinase R, ATF4 upregulation, and NOXA activation, ultimately resulting in MCL-1 degradation. These combination therapies warrant further consideration and investigation in the search for a more comprehensive treatment strategy for AML.

Keywords: acute myeloid leukemia; anti-cancer activity; combination therapy; cytarabine; drug resistance; liposomal drug encapsulation; nanocarrier drug delivery; sphingosine kinase 1 inhibitors; targeted cancer therapy; venetoclax.

Grants and funding

T.M.N.’s contribution to this research was supported by an Early Career Fellowship from the National Health and Medical Research Council of Australia (APP1138079), the University of South Australia Research Themes Investment Scheme, and the University of South Australia DVCRE Research Seed Funding. P.J.’s contribution to the research was undertaken with the financial support of the Cancer Council’s Beat Cancer Project on behalf of its donors and the State Government through the Department of Health and Wellbeing.