Abstract
Patients with Non‐Hodgkin lymphoma (NHL) treated by conventional chemotherapeutic drugs usually require a long recovery period. However, metronomic combination chemotherapy (MCC) enhances therapeutic efficacy and decreases side effects in the treatment of NHL. In this study, we tested and compared the effects of metronomic chemotherapy (MC) using podophyllotoxin derivative etoposide (VP‐16) alone and that of MCC using both VP‐16 and everolimus (RAD001) in the treatment of NHL. Two types of NHL cells, OCI‐LY‐10 and SU‐DHL‐6, were employed for the experiments. Cell proliferation, apoptosis, and cell senescence were measured to test the effects of drugs in each experiment. In addition, the influences of MC and MCC on the cell cycle and autophagy pathway were evaluated to study the functional mechanisms behind their effects. Finally, we conducted analyses of the growth inhibitory effect and synergistic activity for different MCC. The results showed that MC using low‐dose VP‐16 alone demonstrated strong treatment effects in terms of inducing apoptosis, cell senescence, and reducing tumor cell proliferation, and this treatment also led to changes of the cell cycle. Compared with MC, MCC using VP‐16 and RAD001 together demonstrated even stronger treatment effects, with both the cell cycle and autophagy‐related proteins being affected. Considering the synergistic activity, our results showed the MCC of VP‐16 48 hours + RAD001 24 hours is the optimal method for treating NHL.
Highlights
Non‐Hodgkin lymphoma (NHL) encompasses a diverse group of malignancies that are distinguished by specific cancer cell characteristics in accordance with each disease subtype associated with different treatments
Conventional chemotherapy with maximum tolerated dose (MTD) has limitations associated with its side effects, including the need for a long period of recovery between treatment cycles.[25]
metronomic chemotherapy” (MC) has demonstrated multiple advantages compared with conventional chemotherapy, including minimal side effects, a shorter drug‐recovery period, and less drug resistance.[26]
Summary
Non‐Hodgkin lymphoma (NHL) encompasses a diverse group of malignancies that are distinguished by specific cancer cell characteristics in accordance with each disease subtype associated with different treatments. Deregulation of the mTOR pathway has been proven to be a factor contributing to various types of cancer,[7] including lymphoma.[8] In addition, researchers reported that the mammalian target of rapamycin (mTOR) pathway governs growth signals associated with diverse processes, including senescence,[9] autophagy,[10] and apoptosis.[11] RAD001 is an inhibitor of the mammalian target of mTOR.[4] Previous studies demonstrated that RAD001 alone had anti‐proliferative effects in various malignancies, including renal cancer, breast cancer, non‐small cell lung cancer, and pancreatic neuroendocrine tumors.[12,13,14,15] studies showed that mTOR inhibitors in combination with other traditional chemotherapeutic agents (cyclophosphamide, doxorubicin, vincristine, prednisone) presented better efficacy in treating NHL.[16,17,18]. We assumed that a synergistic effect on NHL occured upon the administration of MCC with VP‐16 and RAD001
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