Enhanced antitumor activity by the combination of dasatinib and combretastatin A-4 in vitro and in vivo

Abstract

Abstract. The present study showed that the combination of dasatinib and combretastatin A-4 (CA-4) exhibited synergistic cytotoxicity in multiple types of cancer, including ovarian, hepatocellular, lung and prostate carcinoma. The enhanced apoptosis induced by dasatinib plus CA-4 was accompanied by a greater extent of mitochondrial depolarization, caspase-3 activation and PARP cleavage in HO-8910 cells. Furthermore, elevated expression of Mcl-1 led to a reduced apoptosis induced by dasatinib plus CA-4, highlighting that downregulated Mcl-1 was necessary for the potentiating effect of dasatinib to CA-4-triggered apoptosis. A clear increase in γ-H2AX expression was observed in the dasatinib + CA-4 group compared with the mono-treatment groups, indicating that dasatinib plus CA-4 may induce double-strand breaks (DSBs) in HO-8910 cells. Moreover, the increased anticancer efficacy of dasatinib combined with CA-4 was further validated in a human HO-8910 ovarian cancer xenograft model in nude mice. Our study is the first to show that the combination of dasatinib with CA-4 could be a novel and promising therapeutic approach for the treatment of cancer. IntroductionCombretastatin A-4 (CA-4), a natural product isolated from the bark of a south african tree combretum caffrum, is a highly effective antiangiogenic agent that causes vascular shutdown, leading to tumor death (1). CA-4 phosphate (CA-4P), a water soluble pro-drug of CA-4, is rapidly dephosphorylated to the active compound CA-4 and shows reversible binding kinetics to tubulin, leading to disruption of microtubular structures (2,3). Although CA-4P is being studied in clinical trials as a vascular disrupting agent, cardiovascular toxicity and neurotoxicity are dose limiting for CA-4P (4,5). These severe side-effects currently represent the main obstacles to broad clinical application of CA-4P (2). Thus, it is important to develop new antitumor combination therapy with lower concentrations of CA-4 and more specificity for tumor endothelial cells than normal endothelial cells to avoid cardiac toxicity from endothelial damage.Tyrosine kinase inhibitors (TKIs) are rapidly being integrated into the management of a variety of malignant diseases (6). Dasatinib, a novel orally bioactive TKI currently used to treat patients with hematologic and solid malignancies, correlated with a combined targeting of PDGFR-β and VEGFR/c-Src signaling pathways (7-9). The Src kinases have multiple substrates that lead to diverse biological effects in cancer cells, including changes in proliferation, motility, invasion, survival and angiogenesis (10). Dasatinib suppresses tumor angiogenesis, invasion, and metastasis by inhibiting Src expression (11). Cardiovascular and hematologic toxicity are dose limiting for dasatinib; thus, it is necessary to develop new anticancer combination therapy with lower concentrations of dasatinib to avoid these major side-effects (12). Dasatinib has shown synergistic anticancer activity in combination with chemotherapeutic agents including paclitaxel, ixabepil...

Design, synthesis, and biological evaluation of 3′,4′,5′‐trimethoxy evodiamine derivatives as potential antitumor agents

“…Some microtubule targeting agents containing TMP structures have been found to inhibit microtubule polymerization and act as effective tumor‐VDAs against cancer. CA4P (Figure 1) (Liang et al, 2016; Quan et al, 2008; Zhang et al, 2013) and its similar OXi4503 (Bothwell et al, 2016), AVE8062 (Sessa et al, 2013), colchicine analog ZD6126 (LoRusso et al, 2008), BNC‐105 (Nowak et al, 2013), CKD‐516 (Lee et al, 2010) all have 3,4,5‐trimethoxyphenyl scaffold. As a pharmacophore of Tumor‐VDAs, Trimethoxyphenyl is retained as the necessary active part, and the bridge chain in the middle can be modified with amide bond, sulfonamide bond, and so on (Herdman et al, 2016; Nguyen et al, 2012; Yan et al, 2015).…”

Combretastatin A4 Regulates Proliferation, Migration, Invasion, and Apoptosis of Thyroid Cancer Cells via PI3K/Akt Signaling Pathway

“…CA4 as an antimitotic agent can strongly cause vascular shutdown and cell death in tumors by binding the colchicine binding site of tubulin to block microtubule assembly [9]. Over the past 2 decades, CA4 and CA4 derivatives have been discovered to confer cytotoxic potency and anti-proliferative activity in a variety of human cancer cells, such as non-small cell lung cancer [10], ovarian cancer [11], and breast cancer cells [12]. In addition, CA4 has demonstrated an anti-metastasis effect in human gastric cancer [13] and bladder cancer cells [14].…”