Table 2.

Recent preclinical studies targeting activating pathway in PEL

Study ref.DrugActivityModelKey findings
77  Berberine NF-κB inhibition In vitro: PEL cell lines Induction of apoptosis and suppressed NF-κB activity by inhibiting IKK phosphorylation 
   In vivo: xenograft mouse model 
83  Thioridazine MALT1 inhibition In vitro: PEL cell lines MALT1 inhibition induced a switch to lytic phase and the reduced growth and survival 
   In vivo: xenograft mouse model 
78  3-AP Ribonucleotide reductase inhibition In vitro: PEL cell lines Induction of cell cycle arrest through the inhibition of NF-κB pathway 
 In vivo: xenograft mouse model 
88  PEP005 Agonist of protein kinase C and activation of NF-κB In vitro: PEL cell lines Combination of PEP005 with BET inhibitor induced HHV8/KSHV lytic replication and the inhibition of IL6 production 
91  PF-04691502, AKTi 1/2 PI3K/AKT/mTOR inhibition In vitro: PEL cell lines Combination of PI3K/AKT/mTOR inhibitor with a glycolytic inhibitor strengthened the cytotoxicity in PEL cells 
89  PF-2341066 c-MET inhibition In vitro: PEL cell lines Induction of G2/M cell cycle arrest and apoptosis of PEL cells in vitro and in vivo 
79  Everolimus mTOR inhibition In vitro: PEL cell lines Induction of caspase-dependent apoptosis and downregulation of HHV8/KSHV latent antigen expression 
93  Tenovin-6 SIRT1 and SIRT2 inhibition In vitro: PEL cell lines Inhibition of cell proliferation and induction of apoptosis through AMPK inactivation 
  In vivo: xenograft mouse model 
80  ABC294640 Sphingosine kinase 2 inhibition In vitro: PEL cell lines Induction of apoptosis through the suppression of HHV8/KSHV-associated signal transduction 
  In vivo: xenograft mouse model 
81  MLN4924 Neddylation inhibitor In vitro: PEL cell lines Induction of viral lytic protein expression 
94  YM155 Survivin inhibition In vitro: PEL cell line; PDX cell Induction of apoptosis through the decreased MCL1 expression 
   In vivo: PDX mouse model 
90  PX-478 HIF-1α inhibition In vitro: PEL cell lines Induction of a dose-dependent decrease in HIF-1α mRNA and reduction of cell proliferation 
92  Metformin Reduction of intracellular ROS In vitro: PEL cell lines Induction of apoptosis through the downregulation of v-FLIP, the reduction of intracellular ROS, the activation of AMPK, the inhibition of mTOR, and the dephosphorylation of STAT3 
82  Chloroquine ER stress activation In vitro: PEL cell lines Induction of ER stress-mediated apoptosis 
   In vivo: xenograft mouse model 
87  IMiDs Immunomodulation In vitro: PEL cell lines Preventing HHV8/KSHV-induced downregulation of MHC-1 surface expression 
86  IMiDs IKZF-IRF4-MYC axis inhibition In vitro: PEL cell lines Induction of cell cycle arrest resulting in the suppression of IRF4 and the rapid degradation of IKZF1, but not IKZF3 
 In vivo: xenograft mouse model 
Study ref.DrugActivityModelKey findings
77  Berberine NF-κB inhibition In vitro: PEL cell lines Induction of apoptosis and suppressed NF-κB activity by inhibiting IKK phosphorylation 
   In vivo: xenograft mouse model 
83  Thioridazine MALT1 inhibition In vitro: PEL cell lines MALT1 inhibition induced a switch to lytic phase and the reduced growth and survival 
   In vivo: xenograft mouse model 
78  3-AP Ribonucleotide reductase inhibition In vitro: PEL cell lines Induction of cell cycle arrest through the inhibition of NF-κB pathway 
 In vivo: xenograft mouse model 
88  PEP005 Agonist of protein kinase C and activation of NF-κB In vitro: PEL cell lines Combination of PEP005 with BET inhibitor induced HHV8/KSHV lytic replication and the inhibition of IL6 production 
91  PF-04691502, AKTi 1/2 PI3K/AKT/mTOR inhibition In vitro: PEL cell lines Combination of PI3K/AKT/mTOR inhibitor with a glycolytic inhibitor strengthened the cytotoxicity in PEL cells 
89  PF-2341066 c-MET inhibition In vitro: PEL cell lines Induction of G2/M cell cycle arrest and apoptosis of PEL cells in vitro and in vivo 
79  Everolimus mTOR inhibition In vitro: PEL cell lines Induction of caspase-dependent apoptosis and downregulation of HHV8/KSHV latent antigen expression 
93  Tenovin-6 SIRT1 and SIRT2 inhibition In vitro: PEL cell lines Inhibition of cell proliferation and induction of apoptosis through AMPK inactivation 
  In vivo: xenograft mouse model 
80  ABC294640 Sphingosine kinase 2 inhibition In vitro: PEL cell lines Induction of apoptosis through the suppression of HHV8/KSHV-associated signal transduction 
  In vivo: xenograft mouse model 
81  MLN4924 Neddylation inhibitor In vitro: PEL cell lines Induction of viral lytic protein expression 
94  YM155 Survivin inhibition In vitro: PEL cell line; PDX cell Induction of apoptosis through the decreased MCL1 expression 
   In vivo: PDX mouse model 
90  PX-478 HIF-1α inhibition In vitro: PEL cell lines Induction of a dose-dependent decrease in HIF-1α mRNA and reduction of cell proliferation 
92  Metformin Reduction of intracellular ROS In vitro: PEL cell lines Induction of apoptosis through the downregulation of v-FLIP, the reduction of intracellular ROS, the activation of AMPK, the inhibition of mTOR, and the dephosphorylation of STAT3 
82  Chloroquine ER stress activation In vitro: PEL cell lines Induction of ER stress-mediated apoptosis 
   In vivo: xenograft mouse model 
87  IMiDs Immunomodulation In vitro: PEL cell lines Preventing HHV8/KSHV-induced downregulation of MHC-1 surface expression 
86  IMiDs IKZF-IRF4-MYC axis inhibition In vitro: PEL cell lines Induction of cell cycle arrest resulting in the suppression of IRF4 and the rapid degradation of IKZF1, but not IKZF3 
 In vivo: xenograft mouse model 

3-AP, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone; AMPK, adenosine monophosphate–activated protein kinase; BET, bromodomain and extraterminal; ER, endoplasmic reticulum; IKZF, Ikaros family zinc finger protein; IMiD, immunomodulatory drug; MALT1, mucosa-associated lymphoid tissue lymphoma translocation protein 1; MCL1, myeloid cell leukemia 1; PDX, patient-derived xenograft; ROS, reactive oxygen species.

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