Vorinostat increases carboplatin and paclitaxel activity in non-small-cell lung cancer cells.
We observed a 53% response rate in non-small cell lung cancer (NSCLC) patients treated with vorinostat plus paclitaxel/carboplatin in a Phase I trial. Studies were undertaken to investigate the mechanism (s) underlying this activity. Growth inhibition was assessed in NSCLC cells by MTT assay after 72 hr of continuous drug exposure. Vorinostat (1 microM) inhibited growth by: 17% +/- 7% in A549, 28% +/- 6% in 128-88T, 39% +/- 8% in Calu1 and 41% +/- 7% in 201T cells. Vorinostat addition to carboplatin or paclitaxel led to significantly greater growth inhibition than chemotherapy alone in all 4 cell lines. Vorinostat (1 microM) synergistically increased the growth inhibitory effects of carboplatin/paclitaxel in 128-88T cells. When colony formation was measured after drug withdrawal, vorinostat significantly increased the effects of carboplatin but not paclitaxel. The % colony formation was control 100%; 1 microM vorinostat, 83% +/- 10%; 5 microM carboplatin, 41% +/- 11%; carboplatin/vorinostat, 8% +/- 4%; 2 nM paclitaxel, 53% +/- 11%; paclitaxel/vorinostat, 46% +/- 21%. In A549 and 128-88T, vorinostat potentiated carboplatin induction of gamma-H2AX (a DNA damage marker) and increased alpha-tubulin acetylation (a marker for stabilized mictrotubules). In A549, combination of vorinostat with paclitaxel resulted in a synergistic increase in alpha-tubulin acetylation, which reversed upon drug washout. We conclude that vorinostat interacts favorably with carboplatin and paclitaxel in NSCLC cells, which may explain the provocative response observed in our clinical trial. This likely involves a vorinostat-mediated irreversible increase in DNA damage in the case of carboplatin and a reversible increase in microtubule stability in the case of paclitaxel.
Owonikoko
Taofeek K
TK
University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Ramalingam
Suresh S
SS
Kanterewicz
Beatriz
B
Balius
Trent E
TE
Belani
Chandra P
CP
Hershberger
Pamela A
PA
D000107:Acetylation / Q000187:drug effects; D000230:Adenocarcinoma / Q000473:pathology; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000473:pathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000473:pathology; D017321:Clinical Trials, Phase I as Topic; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D009363:Neoplasm Proteins / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism; D014410:Tumor Stem Cell Assay; D000077337:Vorinostat
D004273:DNA, Neoplasm; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D009363:Neoplasm Proteins; D014404:Tubulin; D000077337:Vorinostat; D016190:Carboplatin; D017239:Paclitaxel