TRAIL and Bortezomib: Killing Cancer with Two Stones

  • Qureshi, Muhammad Zahid (Department of Chemistry, GCU Lahore) ;
  • Romero, Mirna Azalea (Laboratorio de Farmacologia, Unidad Academica de Medicina, Universidad Autonoma de Guerrero) ;
  • Attar, Rukset (Department of Obstetrics and Gynecology, Yeditepe University Faculty of Medicine) ;
  • Javed, Zeeshan (Chughtais Lahore Lab, Rashid Latif Medical College) ;
  • Farooqi, Ammad Ahmad (Laboratory for Translational Oncology and Personalized Medicine, Rashid Latif Medical College)
  • Published : 2015.03.09


Cancer genomics and proteomics have undergone considerable broadening in the past decades and increasingly it is being realized that solid/liquid phase microarrays and high-throughput resequencing have provided platforms to improve our existing knowledge of determinants of cancer development, progression and survival. Loss of apoptosis is a widely and deeply studied process and different approaches are being used to restore apoptosis in resistant cancer phenotype. Modulating the balance between pro-apoptotic and anti-apoptotic proteins is essential to induce apoptosis. It is becoming more understood that pharmacological inhibition of the proteasome might prove to be an effective option in improving TRAIL induced apoptosis in cancer cells. Keeping in view rapidly accumulating evidence of carcinogenesis, metastasis, resistance against wide ranging therapeutics and loss of apoptosis, better knowledge regarding tumor suppressors, oncogenes, pro-apoptotic and anti-apotptic proteins will be helpful in translating the findings from benchtop to bedside.




  1. Bosman MC, Schuringa JJ, Quax WJ, Vellenga E (2013). Bortezomib sensitivity of acute myeloid leukemia CD34(+) cells can be enhanced by targeting the persisting activity of NF-${\kappa}B$ and the accumulation of MCL-1. Exp Hematol, 41, 530-8.
  2. Bross PF, Kane R, Farrell AT, et al (2004). Approval summary for bortezomib for injection in the treatment of multiple myeloma. Clin Cancer Res, 10, 3954-64.
  3. Bullenkamp J, Raulf N, Ayaz B, et al (2014). Bortezomib sensitises TRAIL-resistant HPV-positive head and neck cancer cells to TRAIL through a caspase-dependent, E6-independent mechanism. Cell Death Dis, 23, 1489.
  4. Bychkov ML, Gasparian ME, Dolgikh DA, Kirpichnikov MP (2014). Combination of TRAIL with bortezomib shifted apoptotic signaling from DR4 to DR5 Death Receptor by selective internalization and degradation of DR4. PLoS One, 9, 109756.
  5. Chauhan D, Catley L, Li G, Podar K, Hideshima T, Velankar M et al. (2005). A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell, 8, 407-19.
  6. Chen KF, Yu HC, Liu CY, et al (2011). Bortezomib sensitizes HCC cells to CS-1008, an antihuman death receptor 5 antibody, through the inhibition of CIP2A. Mol Cancer Ther, 10, 892-901.
  7. Gillissen B, Richter A, Richter A, Overkamp T, Essmann F, Hemmati PG, Preissner R, Belka C, Daniel PT (2013). Targeted therapy of the XIAP/proteasome pathway overcomes TRAIL-resistance in carcinoma by switching apoptosis signaling to a Bax/Bak-independent 'type I' mode. Cell Death Dis, 23, 643.
  8. Kahana S, Finniss S, Cazacu S, et al (2011). Proteasome inhibitors sensitize glioma cells and glioma stem cells to TRAILinduced apoptosis by $PKC{\varepsilon}$-dependent downregulation of AKT and XIAP expressions. Cell Signal, 23, 1348-57.
  9. Koschny R, Boehm C, Sprick MR, et al (2014). Bortezomib sensitizes primary meningioma cells to TRAIL-induced apoptosis by enhancing formation of the death-inducing signaling complex. J Neuropathol Exp Neurol, 73, 1034-46.
  10. Laussmann MA, Passante E, Hellwig CT, (2012). Proteasome inhibition can impair caspase-8 activation upon submaximal stimulation of apoptotic tumor necrosis factor-related apoptosis inducing ligand (TRAIL) signaling. J Biol Chem, 287, 14402-11.
  11. Loi M, Becherini P, Emionite L, et al (2014). sTRAIL coupled to liposomes improves its pharmacokinetic profile and overcomes neuroblastoma tumour resistance in combination with Bortezomib. J Control Release, 28, 157-66.
  12. Rapino F, Naumann I, Fulda S (2013). Bortezomib antagonizes microtubule-interfering drug-induced apoptosis by inhibiting G2/M transition and MCL-1 degradation. Cell Death Dis, 21, 925.
  13. Somasekharan SP, Koc M, Morizot A, et al (2013). TRAIL promotes membrane blebbing, detachment and migration of cells displaying a dysfunctional intrinsic pathway of apoptosis. Apoptosis, 18, 324-36.
  14. Tuthill MH, Montinaro A, Zinngrebe J, et al (2014). TRAIL-R2-specific antibodies and recombinant TRAIL can synergise to kill cancer cells. Oncogene. [Epub ahead of print].
  15. Unterkircher T, Cristofanon S, Vellanki SH, Nonnenmacher L, Karpel-Massler G, Wirtz CR, Debatin KM, Fulda S (2011). Bortezomib primes glioblastoma, including glioblastoma stem cells, for TRAIL by increasing tBid stability and mitochondrial apoptosis. Clin Cancer Res, 17, 4019-30.
  16. Xu L, Su L, Liu X (2012). $PKC{\delta}$ regulates death receptor 5 expression induced by PS-341 through ATF4-ATF3/CHOP axis in human lung cancer cells. Mol Cancer Ther, 11, 2174-82.
  17. Yuan BZ, Chapman J, Ding M, et al (2013). TRAIL and proteasome inhibitors combination induces a robust apoptosis in human malignant pleural mesothelioma cells through Mcl-1 and Akt protein cleavages. BMC Cancer, 22, 140.
  18. Zhao B, Li L, Cui K, et al (2011). Mechanisms of TRAIL and gemcitabine induction of pancreatic cancer cell apoptosis. Asian Pac J Cancer Prev, 12, 2675-8.

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