Roy Chowdhury 2018 J Thorac Oncol
|Roy Chowdhury S, Saleh R, Girard C, Peltier C, Desautels D, Dawe D, Banerji V, Banerji S (2018) Targeting mitochondrial metabolism as a selective therapeutic approach in small cell lung cancer (SCLC). J Thorac Oncol.|
Link: Open Access
Event: J Thorac Oncol
SCLC accounts for 13% of new lung cancer diagnoses and is the most aggressive form of the disease. Altered cellular metabolism is considered a hallmark of cancer and a target for therapeutic intervention. Mitochondria represent an important cellular compartment and selectively targeting mitochondrial bioenergetics may be an effective therapeutic approach for SCLC. Nicotinamidephospho-robosyltransferase (NAMPT) is a key enzyme in the mitochondrial nicotinamide adenine dinucleotide salvage pathway. Recent high-throughput drug screens identified SCLC as the most sensitive cancer subtype to NAMPT inhibitors like FK866. Genomic studies of SCLC have also suggested the constitutive activation of the PI3K/AKT/mTOR pathway in a significant portion of SCLC cases. Idelalisib a phosphatidylinositol-3-kinase-delta inhibitor is approved for the treatment of B-cell malignancies. We hypothesize that the inhibitors FK866 and idelalisib will alter SCLC mitochondrial bioenergetic profiles and function, and that combination therapy may enable lower drug doses in clinical use.
Mitochondrial bioenergetics profiles at baseline and in response to drug were assessed in SCLC cell lines H69, DMS79, and H209 using a high resolution Oroboros Oxygraph 2K. Corresponding cell survival was determined using ATP glow and flow cytometry. Western blot analysis was used to evaluate cell death pathways.
Cell survival and mitochondrial bioenergetics parameters i.e. basal respiration, maximal respiration, spare respiratory capacity, and respiratory control ratio were measured in a dose-dependent manner for FK866 (0.5 – 2.5 nM) and idelalisib (1 – 50 μM) at 24 and 48 hours in SCLC. The IC50 for cell survival with FK866 in the 3 lines ranged between 1 and 8 nM. FK866 did not induce apoptosis as measured by Caspase 3 cleavage, but induced γH2X phosphorylation suggesting a role for DNA damage at lethal doses. Mitochondrial bioenergetics was inhibited as low as 0.5 nM dose of FK866 and 6.25 μM of idelalisib. Our preliminary data also demonstrate that the combination of 1 nM FK866 and 6.25 μM idelalisib significantly decreases the major mitochondrial bioenergetic parameters compared to FK866 alone after 24 or 48 hours treatment.
Both FK866 and idelalisib affected bioenergetics profile in SCLC cells and the combined effect of both drugs is on the mitochondrial bioenergetics profile is greater than the impact of single agents. The combined use of these drugs at lower doses targeting mitochondrial metabolism may allow for a greater therapeutic index in clinical trials.
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Cancer
Organism: Human Tissue;cell: Lung;gill
Roy Chowdhury S(1), Saleh R(1), Girard C(1), Peltier C (1), Desautels D(2), Dawe D(2), Banerji V(1), Banerji S(2)
- Cancercare Manitoba
- Medical Oncology, Cancercare Manitoba; Winnipeg, MB/CA