Oxaliplatin is clinically compelling because of severe peripheral neuropathy. The side effect can result in dosage reductions or even cessation of chemotherapy, and no effective treatments are available. AC591 is a standardized extract of Huangqi Guizhi Wuwu decoction, an herbal formula recorded in “Synopsis of the Golden Chamber” for improving limb numbness and pain. In this study, we investigated whether AC591 could protect against oxaliplatin-induced peripheral neuropathy. To clarify it, a rat model of oxaliplatin-induced peripheral neuropathy was established, and neuroprotective effect of AC591 was studied. Our results showed that pretreatment with AC591 reduced oxaliplatin-induced cold hyperalgesia, mechanical allodynia as well as morphological damage of dorsal root ganglion. Microarray analysis indicated the neuroprotective action of AC591 depended on the modulation of multiple molecular targets and pathways involved in the downregulation of inflammation and immune response. Moreover, AC591 enhanced the antitumor activity of oxaliplatin to some extent in Balb/c mice bearing CT-26 carcinoma cells. The efficacy of AC591 is also investigated in 72 colorectal cancer patients. After four cycles of treatment, the percentage of grades 1–2 neurotoxicity in AC591-treated group (n = 36) was 25%, whereas in the control group the incidence was 55.55% (P < 0.01) (n = 36). No significant differences in the tumor response rate between the two groups were found. These evidences suggested that AC591 can prevent oxaliplatin-induced neuropathy without reducing its antitumor activity, and may be a promising adjuvant to alleviate sensory symptoms in clinical practice.

Malignant gliomas, the most common subtype of primary brain tumors, are characterized by high proliferation, great invasion, and neurological destruction and considered to be the deadliest of human cancers. Analgesic-antitumor peptide (AGAP), one of scorpion toxic polypeptides, has been shown to have antitumor activity. Here, we show that recombinant AGAP (rAGAP) not only inhibits the proliferation of gliomas cell SHG-44 and rat glioma cell C6, but also suppresses the migration of SHG-44 cells during wound healing. To explain these phenomena, we find that rAGAP leads to cell cycle of SHG-44 arrested in G1 phase accompanied by suppressing G1 cell cycle regulatory proteins CDK2, CDK6, and p-RB by means of the down-regulated protein expression of p-AKT. Meanwhile, rAGAP significantly decreases the production of NF-κB, BCL-2, p-p38, p-c-Jun, and p-Erk1/2 and further suppresses the activation of VEGF and MMP-9 in SHG-44 cells. These findings suggest rAGAP inhibit proliferation and migration of SHG-44 cells by arresting cell cycle and interfering p-AKT, NF-κB, BCL-2, and MAPK signaling pathways.

Luteolin has been shown to have a strong anticancer effect on various cancer models via programmed cell death (apoptosis). However, the fundamental mechanisms of these effects are still unclear. In the present study, we examined the question of whether or not luteolin can inhibit proliferation of pancreatic carcinoma cells, via apoptosis. We used three human pancreatic carcinoma cell lines, PANC-1, CoLo‑357 and BxPC-3 in our study. In luteolin-treated pancreatic carcinoma cells, typical features of apoptosis were observed. Luteolin increased the expression of the pro-apoptotic protein Bax and decreased the expression of the anti-apoptotic protein Bcl-2, with a concomitant increase in the levels of caspase-3 and cleaved PARP after treatment for 24 h. Luteolin inhibited HUVEC proliferation and vessel growth in CAM in vivo. In addition, the concentration of VEGF in the conditioned medium from human pancreatic carcinoma cells was downregulated by luteolin. Pancreatic carcinoma cells, pretreated with luteolin, could decrease the capillary-like structure formation by HUVEC, which was analyzed by a co-culture system. The abatement of VEGF secretion was related to the inhibition of VEGF mRNA expression, which may be regulated by inhibiting the transcription activity of nuclear transcription factor NF-κB.

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Prolyl 4-hydroxylase alpha subunit is the enzymic active site of prolyl 4-hydroxylase, which is a critical enzyme to maintain the stability of newly synthesized collagens. The expression profile and functional role of P4HA3 in gastric cancer have not been explored. In the Cancer Genome Atlas-Stomach Cancer, P4HA3 RNA is significantly upregulated in gastric cancer than in normal stomach tissues. In the Human Protein Atlas, Prolyl 4-hydroxylase alpha subunit is not detectable by immunohistochemistry staining in normal stomach tissues, but it has weak staining in 7 of 12 gastric cancer tissues. Further study showed that SNAI2 (encoding Slug) is highly coexpressed with P4HA3 (Pearson r = 0.70) in Cancer Genome Atlas-Stomach Cancer. In vitro cell assay showed that Slug could efficiently bind to the P4HA3 promoter and increase its transcription. P4HA3 exon array data in Cancer Genome Atlas-Stomach Cancer revealed that 2 exons are significantly upregulated in M1 (N = 27) cases than in M0 (N = 367) cases. In MKN-45 and AGS cells, P4HA3 upregulation could enhance cell motility and invasiveness. In Cancer Genome Atlas-Stomach Cancer, high P4HA3 exon expression is associated with significantly worse 5-year and 10-year overall survival (P = .007 and .009, respectively). Data mining in Kaplan-Meier plotter also showed that high P4HA3 expression is related to unfavorable overall survival (hazard ratio: 1.54, 95% confidence interval: 1.23-1.93, P < .001) and first progression-free survival (hazard ratio: 1.64, 95% confidence interval: 1.29-2.1, P < .001). Based on findings above, we infer that P4HA3 is epigenetically activated by Slug, and its deregulation is associated with enhanced metastasis and poor survival of gastric cancer.