46021_1_supp_1_l0z6ns.doc 1 Supplementary Table S1. Preclinical studies of combinations of bortezomib and novel targeted agents being evaluated in clinical trials Class/agent Cell lines/xenograft models Combination activity and possible mechanism of action Reference HDAC inhibitors Vorinostat U266 and MM.1S cells, and CD138+ patient bone marrow cells Synergistic apoptosis/cytotoxicity; increased ROS generation resulting in mitochondrial dysfunction, caspase-3, -8, and -9 activation, NF-κB inhibition, JNK activation, and p53 induction Pei et al. (1) Jeko-1 and Granta-519 cells Markedly increased ROS generation and decreased NF-κB activity Heider et al. (2) Hodgkin’s lymphoma cell lines HD- LM2, L-428, and KM-H2 Increased apoptosis; inhibition of Stat6, Akt, and ERK Georgakis et al. (3) NSCLC: NCI-H157, NCI-H358, NCI- H460, and NCI-A549 Induced apoptosis through generation of ROS Denlinger et al. (4) Pancreatic cancer cells and orthotopic pancreatic cancer xenograft model Aggresome disruption, resulting in ER stress and synergistic apoptosis Nawrocki et al. (5) Hepatoma cells: HepG2 and Huh6 Synergistic apoptosis and increased expression of c-Jun, phosphor-c- Jun, and FasL, and production of Bcl-Xs Emanuele et al. (6) Murine SCID-hu xenograft LAGlambda-1 model Slight inhibition of tumor growth and reduction of paraprotein levels Campbell et al. (7) Belinostat Osteoclasts, MM.1S, RPMI-8226, OPM2 cell lines and xenograft murine model Synergistic inhibition of osteoclastogenesis; greater inhibition of MM cell proliferation, increased apoptosis and cell death – greater caspase cleavage; increased xenograft tumor inhibition Feng et al. (8) HNSCC cell lines and bortezomib- resistant UMSCC-11A xenografts NF-κB inhibition; increased antitumor activity Duan et al. (9)
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Supplementary Table S1. Preclinical studies of combinations of bortezomib and novel targeted agents being evaluated in clinical trials
Class/agent Cell lines/xenograft models Combination activity and possible mechanism of action Reference
HDAC inhibitors
Vorinostat U266 and MM.1S cells, and
CD138+ patient bone marrow cells
Synergistic apoptosis/cytotoxicity; increased ROS generation resulting in
mitochondrial dysfunction, caspase-3, -8, and -9 activation, NF-κB
inhibition, JNK activation, and p53 induction
Pei et al. (1)
Jeko-1 and Granta-519 cells Markedly increased ROS generation and decreased NF-κB activity Heider et al. (2)
Hodgkin’s lymphoma cell lines HD-
LM2, L-428, and KM-H2
Increased apoptosis; inhibition of Stat6, Akt, and ERK Georgakis et al.
(3)
NSCLC: NCI-H157, NCI-H358, NCI-
H460, and NCI-A549
Induced apoptosis through generation of ROS Denlinger et al.
(4)
Pancreatic cancer cells and
orthotopic pancreatic cancer
xenograft model
Aggresome disruption, resulting in ER stress and synergistic apoptosis Nawrocki et al.
(5)
Hepatoma cells: HepG2 and Huh6 Synergistic apoptosis and increased expression of c-Jun, phosphor-c-
Jun, and FasL, and production of Bcl-Xs
Emanuele et al.
(6)
Murine SCID-hu xenograft
LAGlambda-1 model
Slight inhibition of tumor growth and reduction of paraprotein levels Campbell et al.
(7)
Belinostat Osteoclasts, MM.1S, RPMI-8226,
OPM2 cell lines and xenograft
murine model
Synergistic inhibition of osteoclastogenesis; greater inhibition of MM cell
proliferation, increased apoptosis and cell death – greater caspase
cleavage; increased xenograft tumor inhibition
Feng et al. (8)
HNSCC cell lines and bortezomib-
resistant UMSCC-11A xenografts
NF-κB inhibition; increased antitumor activity Duan et al. (9)
46021_1_supp_1_l0z6ns.doc 2
LBH589
Panobinostat
RPMI8226, MM.1S and OPM1 cells
and CD138-selected patient cells;
KMS-12PE, KMS-18, LP-1, NCI
H929, KMS-11, RPMI8226, OPM-2,
and U266 and 1S-luciferase tumor
mouse model
Formation of abnormal bundles of hyperacetylated α-tubulin, plus
diminished aggresome size; induces apoptosis
Catley et al.
(10);
Growney et al.
(11)
Depsipeptide
romidepsin
Human myeloid leukemia cell lines
HL-60 and K562 Activation of the mitochondrial apoptotic pathway; translocation of the
proapoptotic Bax, cytochrome c release
Sutheesophon
et al. (12)
Kinase inhibitors
Flavopiridol Bcr/Abl- human leukemia cells
Promotes bortezomib-mediated downregulation and apoptosis.
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