Fumonisin B1 Inhibits Endoplasmic Reticulum Stress Associated-apoptosis After FoscanPDT Combined with C6-Pyridinium Ceramide or Fenretinide.
Combining an anticancer agent fenretinide (HPR) or C6-pyridinium ceramide (LCL29) with Foscan-mediated photodynamic therapy (FoscanPDT) is expected to augment anticancer benefits of each substance. We showed that treatment with FoscanPDT+HPR enhanced accumulation of C16-dihydroceramide, and that fumonisin B1 (FB), an inhibitor of ceramide synthase, counteracted caspase-3 activation and colony-forming ability of head and neck squamous cell carcinoma (HNSCC) cells. Because cancer cells appear to be more susceptible to increased levels of the endoplasmic reticulum (ER) stress than normal cells, herein we tested the hypothesis that FoscanPDT combined with HPR or LCL29 induces FB-sensitive ER stress-associated apoptosis that affects cell survival.



Using an HNSCC cell line, we determined: cell survival by clonogenic assay, caspase-3 activity by spectrofluorometry, the expression of the ER markers BiP and CHOP by quantitative real-time polymerase chain reaction and western immunoblotting, and sphingolipid levels by mass spectrometry.



Similar to HPR+FoscanPDT, LCL29+FoscanPDT induced enhanced loss of clonogenicity and caspase-3 activation, that were both inhibited by FB. Our additional pharmacological evidence showed that the enhanced loss of clonogenicity after the combined treatments was singlet oxygen-, ER stress- and apoptosis-dependent. The combined treatments induced enhanced, FB-sensitive, up-regulation of BiP and CHOP, as well as enhanced accumulation of sphingolipids.



Our data suggest that enhanced clonogenic cell killing after the combined treatments is dependent on oxidative- and ER-stress, apoptosis, and FB-sensitive sphingolipid production, and should help develop more effective mechanism-based therapeutic strategies.
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, U.S.A.
Nithin B
NB
Boppana
Department of Pediatrics Division of Hematology-Oncology, Charles Darby Children's Research Institute, and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, U.S.A.
Jacqueline M
JM
Kraveka
Department of Pediatrics Division of Hematology-Oncology, Charles Darby Children's Research Institute, and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, U.S.A.
Mehrdad
M
Rahmaniyan
Department of Pediatrics Division of Hematology-Oncology, Charles Darby Children's Research Institute, and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, U.S.A.
L I
LI
Li
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, U.S.A.
Alicja
A
Bielawska
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, U.S.A.
Jacek
J
Bielawski
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, U.S.A.
Jason S
JS
Pierce
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, U.S.A.
Jeremy S
JS
Delor
Center for Molecular Medicine and Genetics and Department of Immunology and Microbiology, Wayne State University School of Medicine, Wayne State University, Detroit, MI, U.S.A.
Kezhong
K
Zhang
British Columbia Cancer Agency, Vancouver, BC, Canada.
Mladen
M
Korbelik
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, U.S.A. jmjilyss999@gmail.com.|Karmanos Cancer Institute, Wayne State University, Detroit, MI, U.S.A.
Duska
D
Separovic
D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D002518:Ceramides / Q000494:pharmacology*; D003131:Combined Modality Therapy; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D017313:Fenretinide / Q000494:pharmacology*; D037341:Fumonisins / Q000494:pharmacology*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008652:Mesoporphyrins / Q000494:pharmacology*; D010778:Photochemotherapy / Q000379:methods*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D000077195:Squamous Cell Carcinoma of Head and Neck
C539200:2-N-(6'-(1''-pyridinium)hexanoyl)sphingosine; D061945:Caspase Inhibitors; D002518:Ceramides; D037341:Fumonisins; D008652:Mesoporphyrins; D011726:Pyridinium Compounds; D011838:Radiation-Sensitizing Agents; D017313:Fenretinide; C056933:fumonisin B1; D053148:Caspase 3; C072269:temoporfin
Apoptosis; ER stress; LCL29; PDT; fenretinide; fumonisin; sphingolipids