Risk of mucocutaneous toxicities in patients with solid tumors treated with sorafenib: an updated systematic review and meta-analysis

We performed a systematic review and meta-analysis of mucocutaneous toxicities associated with sorafenib, an oral multi tyrosine kinase inhibitor. Eligible studies included randomized Phase II and III trials of patients with solid tumors on sorafenib daily describing events of hand foot skin reaction, skin rash, alopecia, stomatitis or pruritis. Patients treated with sorafenib had a significantly increased risk of all-grade mucocutaneous toxicities. The RR of all-grade hand foot skin reaction, skin rash, alopecia, stomatitis and pruritis were 4.33 (95% CI: 3.06–6.14), 2.67 (95% CI: 1.86–3.83), 3.93 (95% CI: 2.07–7.45), 2.9 (95% CI: 2.26–3.73), 2.29 (95% CI: 1.87–3.03); respectively. Exploratory subgroup analysis showed no effect of tumor types or treatment regimen (monotherapy versus combination) on the RR of mucocutaneous toxicities. Our meta-analysis has demonstrated that sorafenib is associated with a higher risk of developing all grade mucocutaneous toxicities compared with control.     

Antiangiogenic approach in soft-tissue sarcomas

Soft-tissue sarcomas (STS) are a group of more than 50 malignancies characterized by their rarity. The most effective treatments available only achieve a response rate (RR) of around 20%. Therefore, new therapeutic strategies are needed. Neoangiogenesis is one of the most fundamental mechanisms in cancer and many studies suggest that it also plays a crucial role in STS. Positive results from two Phase III trials in STS with drugs that target angiogenesis have recently been reported, showing an increase in progression-free survival. These data, although promising, are still insufficient and further investigations are needed. STS are unusual among solid tumors, in which single agent angiogenesis inhibitors produce a significant benefit. Unfortunately, we are currently not able to reliably define according to the histological subtype who are the patients that may benefit from this strategy. Moreover, it is clear that single agent treatment is insufficient, hence the current focus is on combination studies.     

索拉非尼联合伊匹单抗对肝癌抑制作用的实验研究

目的探讨索拉非尼联合伊匹单抗对肝癌的抑制作用。方法设置索拉非尼组、伊匹单抗组及联合组,分别加入不同浓度的索拉非尼(5、10、15、20μmol/L)、伊匹单抗(5、10、15、20μmol/L)及两药联合(10μmol/L索拉非尼+10μmol/L伊匹单抗)处理肝癌HepG2细胞。采用CCK-8法检测细胞活力,流式细胞术检测细胞凋亡率,Transwell法检测细胞侵袭能力,蛋白质印迹(Western blot)法检测Raf-1、磷酸化丝裂原活化蛋白激酶1(p-MEK1)、磷酸化细胞外信号调节激酶1(p-ERK1)蛋白表达量。结果不同浓度索拉非尼、伊匹单抗处理HepG2细胞,随着浓度增加,细胞吸光度值及增殖率均下降,差异均有统计学意义(P﹤0.05)。10μmol/L索拉非尼组、10μmol/L伊匹单抗组以及联合组的细胞增殖率分别为(49.83±0.4)%、(45.53±0.8)%、(33.57±0.9)%,分别低于对照组的100%,差异均有统计学意义(P﹤0.05)。与对照组、10μmol/L索拉非尼组、10μmol/L伊匹单抗组比较,联合组细胞侵袭数目均明显减少,凋亡率均明显提高,Raf-1、p-MEK1、p-ERK1蛋白表达量均明显下调,差异均有统计学意义(P﹤0.01)。结论索拉非尼及伊匹单抗均能显著抑制肝癌HepG2细胞增殖与侵袭,与抑制Raf-1/MEK1/ERK1信号通路有关,且联合给药优于单药。     

HIF‐1α triggers long‐lasting glutamate excitotoxicity via system xc− in cerebral ischaemia–reperfusion

Hypoxia‐inducible factor 1α (HIF ‐1α) controls many genes involved in physiological and pathological processes. However, its roles in glutamatergic transmission and excitotoxicity are unclear. Here, we proposed that HIF ‐1α might contribute to glutamate‐mediated excitotoxicity during cerebral ischaemia–reperfusion (CIR ) and investigated its molecular mechanism. We showed that an HIF ‐1α conditional knockout mouse displayed an inhibition in CIR ‐induced elevation of extracellular glutamate and N ‐methyl‐d ‐aspartate receptor (NMDAR ) activation. By gene screening for glutamate transporters in cortical cells, we found that HIF ‐1α mainly regulates the cystine–glutamate transporter (system x_c^?) subunit xCT by directly binding to its promoter; xCT and its function are up‐regulated in the ischaemic brains of rodents and humans, and the effects lasted for several days. Genetic deletion of xCT in cortical cells of mice inhibits either oxygen glucose deprivation/reoxygenation (OGDR ) or CIR ‐mediated glutamate excitotoxicity in vitro and in vivo . Pharmaceutical inhibition of system x_c^? by a clinically approved anti‐cancer drug, sorafenib, improves infarct volume and functional outcome in rodents with CIR and its therapeutic window is at least 3 days. Taken together, these findings reveal that HIF ‐1α plays a role in CIR ‐induced glutamate excitotoxicity via the long‐lasting activation of system x_c^?‐dependent glutamate outflow and suggest that system x_c^? is a promising therapeutic target with an extended therapeutic window in stroke. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Activation of AMP‐activated protein kinase by retinoic acid sensitizes hepatocellular carcinoma cells to apoptosis induced by sorafenib

To improve the outcome of cancer chemotherapy, strategies to enhance the efficacy of anticancer drugs are required. Sorafenib is the only drug to prolong overall survival of the patients with hepatocellular carcinoma (HCC), however, the outcome is still not satisfactory. Retinoids, vitamin A derivatives, have been known to exhibit inhibitory effects on various cancers including HCC. In this study, we investigated the effects of combined treatment using sorafenib and retinoids including all‐trans retinoic acid (ATRA), NIK‐333, and Am80 on HCC cells. Cell viability assays in six HCC cell lines, HepG2, PLC/PRF/5, HuH6, HLE, HLF, and Hep3B, revealed that 5 and 10 μM ATRA, concentrations that do not exert cytotoxic effects, enhanced the cytotoxicity of sorafenib, being much more effective than NIK‐333 and Am80. We found that ATRA induced AMP‐activated protein kinase activation, which was followed by reduced intracellular ATP level. Gene expression analysis revealed that ATRA decreased the expression of glycolytic genes such as GLUT‐1 and LDHA. In the combination treatment using ATRA and sorafenib, increased apoptosis, followed by the activation of p38 MAPK and JNK, the upregulation and translocation of Bax to mitochondria, and the activation of caspase‐3, was observed. Suppression of AMP‐activated protein kinase by siRNA restored the viability of the cells treated with ATRA and sorafenib. Our results thus indicate that ATRA is useful for enhancing the cytotoxicity of sorafenib against HCC cells by regulating the energy metabolism of HCC cells.     

Fisetin,a phytochemical,potentiates sorafenib-induced apoptosis and abrogates tumor growth in athymic nude mice implanted with BRAF-mutated melanoma cells

Melanoma is the most deadly form of cutaneous malignancy, and its incidence rates are rising worldwide. In melanoma, constitutive activation of the BRAF/MEK/ERK (MAPK) and PI3K/AKT/mTOR (PI3K) signaling pathways plays a pivotal role in cell proliferation, survival and tumorigenesis. A combination of compounds that lead to an optimal blockade of these critical signaling pathways may provide an effective strategy for prevention and treatment of melanoma. The phytochemical fisetin is known to possess anti-proliferative and pro-apoptotic activities. We found that fisetin treatment inhibited PI3K signaling pathway in melanoma cells. Therefore, we investigated the effect of fisetin and sorafenib (an RAF inhibitor) alone and in combination on cell proliferation, apoptosis and tumor growth. Combination treatment (fisetin + sorafenib) more effectively reduced the growth of BRAF-mutated human melanoma cells at lower doses when compared to individual agents. In addition, combination treatment resulted in enhanced (i) apoptosis, (ii) cleavage of caspase-3 and PARP, (iii) expression of Bax and Bak, (iv) inhibition of Bcl2 and Mcl-1, and (v) inhibition of expression of PI3K, phosphorylation of MEK1/2, ERK1/2, AKT and mTOR. In athymic nude mice subcutaneously implanted with melanoma cells (A375 and SK-MEL-28), we found that combination therapy resulted in greater reduction of tumor growth when compared to individual agents. Furthermore, combination therapy was more effective than monotherapy in: (i) inhibition of proliferation and angiogenesis, (ii) induction of apoptosis, and (iii) inhibition of the MAPK and PI3K pathways in xenograft tumors. These data suggest that simultaneous inhibition of both these signaling pathways using combination of fisetin and sorafenib may serve as a therapeutic option for the management of melanoma.     

Sorafenib,a multikinase inhibitor,induces formation of stress granules in hepatocarcinoma cells

Stress granules (SGs) are cytoplasmic RNA multimeric bodies that form under stress conditions known to inhibit translation initiation. In most reported stress cases, the formation of SGs was associated with the cell recovery from stress and survival. In cells derived from cancer, SGs formation was shown to promote resistance to either proteasome inhibitors or 5-Fluorouracil used as chemotherapeutic agents. Despite these studies, the induction of SGs by chemotherapeutic drugs contributing to cancer cells resistance is still understudied. Here we identified sorafenib, a tyrosine kinase inhibitor used to treat hepatocarcinoma, as a potent chemotherapeutic inducer of SGs. The formation of SGs in sorafenib-treated hepatocarcionoma cells correlates with inhibition of translation initiation; both events requiring the phosphorylation of the translation initiation factor eIF2α. Further characterisation of the mechanism of sorafenib-induced SGs revealed PERK as the main eIF2α kinase responsible for SGs formation. Depletion experiments support the implication of PERK-eIF2α-SGs pathway in hepatocarcinoma cells resistance to sorafenib. This study also suggests the existence of an unexpected complex regulatory balance between SGs and phospho-eIF2α where SGs dampen the activation of the phospho-eIF2α-downstream ATF4 cell death pathway.     

索拉非尼联合经肝动脉化疗栓塞术治疗原发性肝细胞癌的疗效和安全性

目的 评估索拉非尼联合经肝动脉化疗栓塞术(TACE)治疗原发性肝癌的疗效和安全性。方法 回顾性分析在中国医科大学附属第一医院介入放射科行索拉非尼系统治疗并联合TACE治疗的10例不可切除肝癌患者的临床资料,按照修订的实体瘤疗效评估标准评价疗效,采用Kaplan-Meier法分析患者生存情况,采用美国国立癌症研究所常见毒性反应分级标准3.0版评价安全性。结果 10例患者中,2例为完全缓解,3例为部分缓解,3例为疾病稳定,2例为疾病进展,中位总生存期为29.5个月。有9例出现不同程度的不良反应,均为3级或以下级别,最常见的不良反应为手足皮肤反应(7/10)和腹泻(6/10)。结论 索拉非尼联合TACE治疗原发性肝癌是一种安全、有效的治疗方法。