Targeting a Nrf2/G6PDH Pathway to Reverse Multi-Drug Resistance in Diffuse Large B-Cell Lymphoma
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Date
2017-05-09
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Abstract
A leading cause of mortality in diffuse large B-cell lymphoma (DLBCL) patients is the development of resistance to the CHOP regimen, the anthracycline-based chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone. Our first objective of this work was to investigate the impact of Nuclear factor erythroid–related factor 2 (Nrf2)/ glucose-6-phosphate dehydrogenase (G6PDH) pathway on CHOP-resistance in DLBCL cell lines. We provide evidence here that a Nrf2/G6PDH pathway plays a role in mediating CHOP-resistance in DLBCL. We found that CHOP-resistant DLBCL cells expressed both higher Nrf2 and G6PDH activities and lower reactive oxygen (predominantly superoxide) levels than CHOP-sensitive cells. We hypothesized that increased activity of the Nrf2/G6PDH pathway leads to higher GSH production, a more reduced state (lower ROS), and CHOP-resistance. In support of our hypothesis, direct inhibition of G6PDH or knockdown of Nrf2/G6PDH lowered both NADPH and GSH levels, increased ROS, and reduced tolerance or CHOP-resistant cells to CHOP. We also present evidence that repeated cycles of CHOP treatment select for a small population of Nrf2^High/G6PDH^High/ROS^Low cells that are more tolerant of CHOP and might be responsible for the emergence of chemoresistant tumors. We propose that sensitive Nrf2^Low /G6PDH^Low /ROS^High cells are essentially killed off by CHOP allowing for the selective propagation of the small population of CHOP-resistant Nrf2^High/G6PDH^High/ROS^Low cells, thereby resulting in relapse of lymphoma.
Our second objective was to study rifamycins’ potency at sensitizing drug resistant cancer cells to chemotherapeutics. We have discovered a novel chemosensitizer (RTI-79, a rifamycinderivative) with a broad spectrum of action that includes ovarian cancer and double and triple hit non-Hodgkin’s lymphoma. RTI-79 is relatively non-toxic and has favorable in vivo safety and pharmacokinetic (PK) profiles. RTI-79 in combination therapies is effective in multiple drug resistant cancers in mouse models. RTI-79 works by dramatically increasing intracellular reactive oxygen species (ROS), primarily superoxide, through redox cycling. The level of ROS induction is directly correlated with drug sensitivity. Importantly, RTI-79 also triggers the unfolded protein response (UPR) that results in increased ubiquitination and loss of Nrf2, the primary sensor for intracellular ROS. Thus, RTI-79 both increases ROS and squelches Nrf2’s ability to respond to ROS. This unique mechanism provides a broad and novel approach for the very safe application of RTI-79, and other rifamycins, in treating drug resistant cancers.
We also showed that RTI-79 acts to increase the oxidative state in chemoresistant cancer cells by inducing superoxide (O2-) and downregulating the Nrf2/G6PDH/NADPH/GSH pathway. RTI-79 also increased the ubiquitination state of several mitochondrial chaperone proteins (mtDnaJ [HSP40]), HSP60, HSP70mt [mortalin]) and decreased activated CREB, which are known to play roles in mitochondrial unfolded protein response (UPRmt) retrograde signaling.
In summary, this research explores a new way to overcome the chemoresistance particularly in DLBCL and ovarian carcinoma. The new findings of this study will significantly impact our understanding of the role of Nrf2/G6PDH signaling pathway in DLBCL, and provide hope for the development of rational therapies for both newly diagnosed patients with DLBCL and also patients with relapsing DLBCL.
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Cancer, drug resistance