Abstract Enhanced expression of anti-apoptotic B-cell lymphoma 2 (BCL-2) protein is frequent in cancer.Targeting of BCL-2 with the specific inhibitor ABT-199 (Venetoclax) has significant clinical activity in malignant diseases such as chronic lymphocytic PHOTOSYNTHETIC PRODUCTIVITY OF LENTIL UNDER T HE ACTION OF BIOLOGICAL PREPARATIONS leukemia and multiple myeloma.The small molecule drug ABT-199 mimics the pro-apoptotic BCL-2 homology domain 3 of BH3-only proteins and blocks the hydrophobic BC-groove in BCL-2.We have previously shown that ABT-199 synergizes with the proteasome inhibitor (PI) bortezomib in soft tissue sarcoma derived cells and cell lines to induce apoptosis.Synergistic apoptosis induction relies on the pore-forming effector BAX and expression of the pro-apoptotic BH3-only protein NOXA.
Bortezomib augments expression of NOXA by blocking its proteasomal degradation.Interestingly, AlphaBoot: accelerated container cold start using SmartNICs shown here for the first time, expression of NOXA is strongly enhanced by ABT-199 induced integrated stress response (ISR).ISR transcription factors ATF3 & ATF4 mediate transactivation of the BH3-only protein NOXA which specifically inhibits the anti-apoptotic MCL-1.Thus, NOXA potentiates the efficacy of the BCL-2 inhibitor ABT-199 by simultaneous inhibition of MCL-1.Hence, ABT-199 has a double impact by directly blocking anti-apoptotic BCL-2 and inhibiting MCL-1 via transactivated NOXA.
By preventing degradation of NOXA PIs synergize with ABT-199.Synergism of ABT-199 and PIs therefore occurs on several, previously unexpected levels.This finding should prompt clinical evaluation of combinatorial regimens in further malignancies.