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1.
J Mol Med (Berl) ; 101(3): 295-310, 2023 03.
Article in English | MEDLINE | ID: mdl-36790532

ABSTRACT

Pancreas ductal adenocarcinoma (PDAC) remains a malignant tumor with very poor prognosis and low 5-year overall survival. Here, we aimed to simultaneously target mitochondria and lysosomes as a new treatment paradigm of malignant pancreas cancer in vitro and in vivo. We demonstrate that the clinically used sphingosine analog FTY-720 together with PAPTP, an inhibitor of mitochondrial Kv1.3, induce death of pancreas cancer cells in vitro and in vivo. The combination of both drugs results in a marked inhibition of the acid sphingomyelinase and accumulation of cellular sphingomyelin in vitro and in vivo in orthotopic and flank pancreas cancers. Mechanistically, PAPTP and FTY-720 cause a disruption of both mitochondria and lysosomes, an alteration of mitochondrial bioenergetics and accumulation of cytoplasmic Ca2+, events that collectively mediate cell death. Our findings point to an unexpected cross-talk between lysosomes and mitochondria mediated by sphingolipid metabolism. We show that the combination of PAPTP and FTY-720 induces massive death of pancreas cancer cells, thereby leading to a substantially delayed and reduced PDAC growth in vivo. KEY MESSAGES: FTY-720 inhibits acid sphingomyelinase in pancreas cancer cells (PDAC). FTY-720 induces sphingomyelin accumulation and lysosomal dysfunction. The mitochondrial Kv1.3 inhibitor PAPTP disrupts mitochondrial functions. PAPTP and FTY-720 synergistically kill PDAC in vitro. The combination of FTY-720 and PAPTP greatly delays PDAC growth in vivo.


Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Sphingomyelin Phosphodiesterase , Sphingomyelins/metabolism , Fingolimod Hydrochloride , Pancreatic Neoplasms/metabolism , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/pathology , Lysosomes/metabolism , Mitochondria/metabolism , Cell Line, Tumor , Pancreatic Ducts/metabolism , Pancreatic Ducts/pathology , Pancreatic Neoplasms
2.
Ann R Coll Surg Engl ; 94(3): e132-3, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22507711

ABSTRACT

Lemierre's syndrome is usually reported in the young and in fit individuals. We report a case of an 81-year-old woman who presented with thrombophlebitis of the internal jugular vein with a pulmonary embolism.


Subject(s)
Acute Pain/etiology , Lemierre Syndrome/diagnostic imaging , Neck Pain/etiology , Aged, 80 and over , Anti-Bacterial Agents/therapeutic use , Anticoagulants/therapeutic use , Diagnosis, Differential , Female , Heparin, Low-Molecular-Weight/therapeutic use , Humans , Lemierre Syndrome/drug therapy , Pulmonary Embolism/drug therapy , Pulmonary Embolism/etiology , Tomography, X-Ray Computed
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