Table 1.
| Protease Inhibitor | Cell Lines | Cell Type | Mechanism | p-Akt Inhibition | Other Observations | Xenograft data | Increased efficacy of chemoradiation therapy? | Ref |
|---|---|---|---|---|---|---|---|---|
| RIT | EL4-T, Jurkat, T1 Meth-A, P815, 3T3 | Thymoma, leukemia, T/B lymphoblastoid hybird, Murine Fibrosarcoma, Murine Mastocytoma, Non transformed fibroblasts | Inhibition of 20S proteasome | Not studied | Apoptosis, accumulation of cell cycle inhibitors | RIT induced growth inhibition in C57BL/6 with ELT-4 tumors | Not studied | 14 |
| SAQ | LnCaP, DU-145, PC-3, U373, K562, Jurkat | Prostate (LnCaP, DU-145, PC-3) Glioblastoma (U373) Leukemia (K562, Jurkat) |
Inhibition of 20S and 26S proteasome, inhibition of NF-κB activity | Not studied | Apoptosis | None | Radiation | 55 |
| RIT, SAQ, NEL, IND | U266, RPMI8226, ARH77 | Multiple myeloma | Inactivation of STAT3 and ERK1/2 | Not studied | Growth arrest, apoptosis, and anti- angiogenesis | None | Not studied | 15 |
| RIT, SAQ, IND | PC-3, DU-145 | Androgen independent prostate | Inhibition of NF-κB binding activity, inhibition of CYP 3A4 by RIT | Not studied | Apoptosis | RIT induced growth inhibition in BNX nu/nu mice with DU145 tumors | Docetaxel | 16 |
| NEL, RIT, SAQ, IND, AMP | SQ20B, T24, MIAPACA2, A549 | SCCa head and neck, Bladder, Pancreatic, Lung | Inhibition of Akt activation | Decreased p-Akt | AMP, NEL induced growth inhibition via decr p-Akt in Ncr nude mice with SQ20B and T24 tumors | Radiation | 45 | |
| NEL, SAQ | HL-60 | Leukemia | Inhibition of 20S proteasome | Not studied | None | Not studied | 57 | |
| NEL, RIT, SAQ, IND, AMP | SW872, LiSa-2, HT1080 | Liposarcoma | Up regulation SREBP-1 expression | Not studied | G1 cell cycle arrest, apoptosis | None | Not studied | 51 |
| SAQ, RIT, NEL IND, AMP, LOP, TAZ | E6 transfected C33A, SiHa | SCCa Cervix | Inhibition of 20S proteasome preventing E6- induced clearance of p53 | Not studied | Apoptosis | None | Not studied | 58 |
| NEL | SQ20B, A549 | SCCa head and neck, Lung | Decreased VEGF expression, decreased hypoxic induction of HIF1α via inactivated Akt pathway | Decreased p-Akt | Increased tumor oxygenation | NEL induced decreased VEGF expression in nude mice with SQ20 or A549 tumors | Radiation | 48 |
| RIT | MCF7, T47D, MDA-MB-436, MDA- MB-231 | Breast cancer | Inhibition of chaparone function of Hsp90 | Decreased p-Akt | G1 arrest, depletion of cyclin dependent kinases 2,4,6 and Cyclin D1, and p-Rb | RIT induced growth inhibition in nude mice with MDA-MB- 231 tumors | Not studied | 49 |
| NEL, SAQ, RIT | H460, H520, A549, EBC-1, ABC-1 | Non small cell lung cancer | Inhibition of Akt activation | Decreased p-Akt | Apoptosis, accumulation of cell cycle inhibitors | NEL induced growth inhibition and increased apoptosis in BALB/c nude mice with H460 tumors | Docetaxel | 40 |
| NEL, SAQ, AMP | NA | Human umbilical vein endotheial cells (HUVEC) | Inhibition of Akt activation | Decreased p-Akt | Apoptosis | NEL induced increased sensitivity to radiation in vascular window model | Radiation | 46 |
| NEL, SAQ, RIT, AMP, TAZ | NCI-60, H157, A549 | NCI-60 (leukemia, lung, colon, CNS, melanoma, ovarian, renal, prostate, breast); H157, A549 Lung | ER stress | Varies among cell lines | G1 cell cycle arrest, apoptosis, autophagy | NEL induced growth inhibtion in BAL/c AnNCr nude mice with H157 tumors | Not studied | 52 |
| NEL | SQ20B | SCCa | Proteasome inhibition, ER stress, and unfolded protein response causing dephosphorylation of p-Akt by PP1 | Decreased p-Akt | None | Radiation | 50 | |
| NEL, RIT, SAQ, IND | 1205 LU, A375, C8161, NIH1286, WM35, WM115 | Melanoma | Cell cycle arrest via inhibition of CDK2, dephosphorylation of Rb; proteasome induced degradation of Cdc25A phosphatase | No change in p- Akt | Growth inhibition and apoptosis | None | Not studied | 53 |
| NEL | U251MG, U87MG | PTEN deficient glioblastoma | Inhibition of Akt activation | Decreased p-Akt, p-S6 | Radiation sensitization in nude mice with U87 tumors | Radiation and temozolomide | 47 | |
| RIT | HUVEC, KSIIM | Normal endothelial cells, KS | Anti-angiogenesis, inhibition of NF-κ B activity | Not studied | Inhibiton of proliferation of HUVEC, inhibition of KS promoting inflammatory proteins | RIT induced growth inhibition in BNX mice with KSIMM tumors | Not studied | 13 |
| NEL, TAZ | T98G, LN229, U251, U87 | Glioblastoma | Proteasome inhibition, ER stress, and unfolded protein response | Not studied | Apoptosis | NEL induced growth inhibition in nude mice with U87 tumors | Not studied | 54 |
| SAQ + Lovastatin | Raj, Daudi | Lymphoma | Proteasome inhibition for both, no data presented | Not studied | Additive effect on growth inhibition | No | Not studied | 56 |
| NEL + Imatinib | IOMM - Lee | Meningioma cell line and Fresh meningioma tissue | Increased Bax:Bcl- 2 and decreased survivin leading to apoptosis | Not studied | Additive effect on growth inhibition | NEL + Imatinib induced growth inhibition in athymic nude mice and IOMM-Lee tumors | Imatinib | 39 |
p-Akt is phosphorylated Akt; Hsp90 is heat shock protein 90
Bold face indicates most active agent
NEL nelfinavir, SAQ saquinavir, RIT ritonavir, IND indinavir, AMP amprenavir, TAZ tazanavir, LOP lopinavir
SCCa is squamous cell carcinoma