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. 2022 Nov 17;53(1):2249948. doi: 10.1002/eji.202249948

Figure 3.

Figure 3

Targeting the TRX system for cancer therapy. Cancer cells adapt to elevated ROS by upregulating cellular antioxidants, including thioredoxin (TRX) and TRX reductase (TRXR), and by downregulating their inhibitor TRX‐interacting protein (TXNIP). The chemotherapeutic drugs auranofin (Au) and PX‐12, which respectively inhibit TRXR and TRX, lead to oxidative stress, reduced 2’‐deoxyribonucleotide (dNTP) biosynthesis and cell death of cancer cells. D‐Allose inhibits cancer cell survival and proliferation by boosting TXNIP expression, which results in the induction of the tumor suppressor p53 and in the inhibition of TRX and of glucose transporter 1 (GLUT1)‐dependent glucose import. Of note, while blockade of TRX or TRXR alone may be sufficient to inhibit T cell leukemia and lymphomas, additional inhibition of the glutathione (GSH)/glutaredoxin (GRX) pathway by the drug buthionine sulfoximine (BSO) may be required to treat B cell malignancies and other tumors due to their redundant functions (e.g. donation of electrons to ribonucleotide reductase [RNR]). Abbreviations: GSR, glutathione reductase; PPP, pentose phosphate pathway; black rectangular boxes indicate chemotherapeutic drugs.