Arsenic Trioxide Suppresses Tumor Growth through Antiangiogenesis via Notch Signaling Blockade in Small-Cell Lung Cancer

Abstract

Small-cell lung cancer (SCLC) is a highly malignant type of lung cancer with no effective second-line chemotherapy drugs. Arsenic trioxide (As2O3) was reported to exert antiangiogenesis activities against lung cancer and induce poor development of vessel structures, similar to the effect observed following the blockade of Notch signaling. However, there are no direct evidences on the inhibitory effects of As2O3 on tumor growth and angiogenesis via blockade of Notch signaling in SCLC. Here, we found that As2O3 significantly inhibited the tumor growth and angiogenesis in SCLC and reduced the microvessel density. As2O3 disturbed the morphological development of tumor vessels and downregulated the protein levels of delta-like canonical Notch ligand 4 (Dll4), Notch1, and Hes1 in vivo. DAPT, a Notch signaling inhibitor, exerted similar effects in SCLC. We found that both As2O3 treatment and Notch1 expression knockdown resulted in the interruption of tube formation by human umbilical vein endothelial cells (HUVECs) on Matrigel. As2O3 had no effects on Dll4 level in HUVECs but significantly inhibited the expression of Notch1 and its downstream gene Hes1 regardless of Dll4 overexpression or Notch1 knockdown. These findings suggest that the antitumor activity of As2O3 in SCLC was mediated via its antiangiogenic effect through the blockade of Notch signaling, probably owing to Notch1 targeting.

Combination therapy: Future directions of immunotherapy in small cell lung cancer

“…And SCLC cells were more sensitive than NSCLC cells to As 2 O 3 , with lower IC 50 values (1 to 2 Amol/L vs. 2 to 5 Amol/L) [ 58 ]. In a word, As 2 O 3 can significantly inhibit SCLC through various mechanisms as follow: 1) induces cytotoxicity via altered redox homeostasis and mitochondrial integrity [ 59 ]; 2) inhibits tumor growth through antiangiogenesis through the blockade of Notch signaling [ 60 ]; 3) inhibits the metastasis by blocking calcineurin-nuclear factor of activated T cells signaling [ 61 ]. However, the results from a phase II clinical trial of As 2 O 3 for the treatment of patients with relapsed SCLC are frustrating.…”

Recent advances and future directions in anti‐tumor activity of cryptotanshinone: A mechanistic review

“…ATO reduces oxygen and nutrient supplies of lung cancer cells to inhibit their growth and proliferation. In this way, ATO suppresses angiogenesis via Notch down‐regulation (Yang, Chang, Li, & Chen, 2019). These studies highlight the anti‐tumor activity of ATO in different cancers.…”

Arsenic intoxication: general aspects and chelating agents

“…In 2001, US FDA and in 2002 EU commission approved an arsenic trioxide drug for its high effectiveness in the treatment of acute and promyelocytic leukemia (Au 2011;Chen et al 2011;Iland and Seymour 2013;Liu et al 2012). Recently As 2 O 3 has also been proposed as a promising candidate for lung cancer treatment, alone or in combination with the classic cisplatin drug (Huang and Zeng 2019;Medici et al 2015;Miodragović et al 2019;Yang et al 2019). The synergic effect of As 2 O 3 with a B cell lymphoma-2 (Bcl-2) family inhibitor (ABT-737) in uterine cervical cancer cells was also evidenced to ameliorate ABT-737 target therapy (Hsin et al 2019).…”