RRx-001 induces apoptosis through reactive oxygen species and endoplasmic reticulum stress in Burkitt lymphoma cells by acting as CD47 and c-Myc regulator.

Burkitt lymphoma (BL) is a highly aggressive non-Hodgkin lymphoma with a poor prognosis in refractory and recurrent patients. RRx-001 is a promising anticancer agent currently under investigation in hematological malignancies; however, its therapeutic effects on BL are not clear. In this study, RRx-001 was found to inhibit the proliferation of BL cells and induce a DNA damage response. RRx-001 can induce apoptosis through caspase cascades with increasing cleavage of Caspases 8, 9, and 3. RRx-001 can also upregulate the expression of DR4, DR5, Bax, and cytochrome C and decrease the expression of Bcl-2, Mcl-1, and XIAP. RRx-001 promotes the accumulation of reactive oxygen species and triggers endoplasmic reticulum (ER) stress in BL cells, both these alterations contribute to RRx-001-induced apoptosis. Additionally, RRx-001 regulates MAPK pathways, and JNK/p38 MAPK signaling functions as a critical hub linking ER stress and oxidative DNA damage. Importantly, RRx-001 also functions as a regulator of CD47 and c-Myc, strongly inhibiting them both in vitro and in a BL cell tumor-bearing mouse model. The overexpression of CD47 increases the proliferation and partially inhibits the apoptosis of BL cells induced by RRx-001. Hence, the findings of this study provided new evidence that RRx-001 may serve as a therapeutic drug for treating BL.