Combined metformin-salicylate treatment provides improved anti-tumor activity and enhanced radiotherapy response in prostate cancer; drug synergy at clinically relevant doses

Autor: Gregory R. Steinberg, Bassem Mekhaeil, Tobias Berg, Theodoros Tsakiridis, Lindsay A. Broadfield, Olga-Demetra Biziotis, Katarina Marcinko, Alexander E. Anagnostopoulos, Paola Muti, Amr Ali, Elham Ahmadi, Panayiotis G. Zacharidis, Aruz Mesci, Evangelia E. Tsakiridis, Kanwaldeep Singh
Rok vydání: 2021
Předmět:
AMPK
Cancer Research
endocrine system diseases
LKB1
Liver Kinase B 1
MET + SAL
metformin and salicylate used together
DNL
de novo lipogenesis
ACC
acetyl-CoA carboxylase
HIF1a
mTOR
the mammalian target of rapamycin
urologic and male genital diseases
OxPhos
oxidative phosphorylation
ECAR
Extracellular Acidification Rate
Prostate cancer
MET
metformin
parasitic diseases
medicine
OCR
oxygen consumption rate
TSC2
Tuberin Sclerosis Complex 2
RC254-282
PI3K/AKT/mTOR pathway
Original Research
Xenografts
PrCa
prostate cancer
Aspirin
P-H3
phosphorylated histone H3
RT
radiotherapy / ionizing irradiation with clinical radiotherapy units
Cell growth
business.industry
Lipogenesis
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
nutritional and metabolic diseases
Histone-H3
HIF1α
hypoxia inducible factor 1
medicine.disease
Metformin
AMPK
AMP-activated protein kinase
HIF1A
4EBP1
Eukaryotic Translation Initiation Factor 4E Binding Protein 1
Oncology
Synergy
mTOR
Cancer research
mTORC1
mTOR complex 1
p70s6k
ribosomal p70 S6 kinase
business
SAL
salicylate
IHC
immunohistochemistry
medicine.drug
Zdroj: Translational Oncology
Translational Oncology, Vol 14, Iss 11, Pp 101209-(2021)
ISSN: 1936-5233
DOI: 10.1016/j.tranon.2021.101209
Popis: Highlights • Combined metformin + salicylate treatment has improved anti-tumor efficacy in prostate cancer. • At clinically achievable doses, it induces increased metabolic stress and sensitizes tumors to radiation. • Metformin + salicylate blocks pathways of de novo lipogenesis and protein synthesis. • In combination with radiation suppresses HIF1a and DNA replication. • This work supports clinical investigation of metformin + salicylate in combination with radiotherapy.
Background There is need for well-tolerated therapies for prostate cancer (PrCa) secondary prevention and to improve response to radiotherapy (RT). The anti-diabetic agent metformin (MET) and the aspirin metabolite salicylate (SAL) are shown to activate AMP-activated protein kinase (AMPK), suppress de novo lipogenesis (DNL), the mammalian target of rapamycin (mTOR) pathway and reduce PrCa proliferation in-vitro. The purpose of this study was to examine whether combined MET+SAL treatment could provide enhanced PrCa tumor suppression and improve response to RT. Methods Androgen-sensitive (22RV1) and resistant (PC3, DU-145) PrCa cells and PC3 xenografts were used to examine whether combined treatment with MET+SAL can provide improved anti-tumor activity compared to each agent alone in non-irradiated and irradiated PrCa cells and tumors. Mechanisms of action were investigated with analysis of signaling events, mitochondria respiration and DNL activity assays. Results We observed that PrCa cells are resistant to clinically relevant doses of MET. Combined MET + SAL treatment provides synergistic anti-proliferative activity at clinically relevant doses and enhances the anti-proliferative effects of RT. This was associated with suppression of oxygen consumption rate (OCR), activation of AMPK, suppression of acetyl-CoA carboxylase (ACC)-DNL and mTOR-p70s6k/4EBP1 and HIF1α pathways. MET + SAL reduced tumor growth in non-irradiated tumors and enhanced the effects of RT. Conclusion MET+SAL treatment suppresses PrCa cell proliferation and tumor growth and enhances responses to RT at clinically relevant doses. Since MET and SAL are safe, widely-used and inexpensive agents, these data support the investigation of MET+SAL in PrCa clinical trials alone and in combination with RT.
Databáze: OpenAIRE
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