1-(2-4-dichlorobenzyl)indazole-3-carbohydrazide and Lung-Neoplasms

Small-cell lung cancer (SCLC), a malignant tumor, is usually widely metastatic when diagnosed. The lack of important therapeutic clinical advances makes it difficult to treat. Previous studies showed that Adjudin had anticancer effects in many other human cancers, and it was synergetic with cisplatin in non-small cell lung cancer. However, the mechanism on SCLC was unclear.. We investigated the potential mechanism and effect of Adjudin on SCLC both in vitro and in vivo.. An SCLC xenograft model showed that Adjudin inhibited tumor growth and was significantly synergetic with paclitaxel (in vitro as well). Cell Counting Kit-8 assays, flow cytometric analysis and western blotting showed that Adjudin effectively suppressed SCLC cell proliferation by inducing S phase arrest and caspase-dependent apoptosis. Moreover, Transwell and scratch assays showed that Adjudin also effectively inhibited migration and invasion. Furthermore, Adjudin activated the sirtuin 3 (SIRT3)-Forkhead box O3a (FOXO3a) pathway. Downregulating SIRT3 or FOXO3a significantly attenuated Adjudin-induced anticancer effects. Furthermore, higher expression of SIRT3 and FOXO3a were positively correlated, and both were associated with longer survival in lung cancer patients.. Overall, the present study is the first to show that Adjudin synergizes with paclitaxel and inhibits cell growth and metastasis by regulating the SIRT3-FOXO3a axis in SCLC; thus, Adjudin has great potential to be an anticancer agent.

Topics: Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Drug Synergism; Female; Forkhead Box Protein O3; Gene Expression Regulation, Neoplastic; Humans; Hydrazines; Indazoles; Lung Neoplasms; Male; Mice; Paclitaxel; Sirtuin 3; Small Cell Lung Carcinoma; Xenograft Model Antitumor Assays

The high mortality of cancer is mainly attributed to multidrug resistance (MDR) and metastasis. A simple micelle system was constructed here to codeliver doxorubicin (DOX), adjudin (ADD), and nitric oxide (NO) for overcoming MDR and inhibiting metastasis. It was devised based on the "molecular economy" principle as the micelle system was easy to fabricate and exhibited high drug loading efficiency, and importantly, each component of the micelles would exert one or more active functions. DOX acted as the main cell killing agent supplemented with ADD, NO, and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). MDR was overcome by synergistic effects of mitochondria inhibition agents, TPGS and ADD. A TPGS-based NO donor can be used as a drug carrier, and it can release NO to enhance drug accumulation and penetration in tumor, resulting in a positive cycle of drug delivery. This DOX-ADD conjugate self-assembly system demonstrated controlled drug release, increased cellular uptake and cytotoxicity, enhanced accumulation at tumor site, and improved in vivo metastasis inhibition of breast cancer. The micelles can fully take advantage of the functions of each component, and they provide a potential strategy for nanomedicine design and clinical cancer treatment.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Delayed-Action Preparations; Doxorubicin; Drug Carriers; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; Hydrazines; Indazoles; Lung; Lung Neoplasms; MCF-7 Cells; Mice; Mice, Inbred BALB C; Micelles; Nanomedicine; Nitric Oxide; Rats; Rats, Sprague-Dawley; Tissue Distribution; Treatment Outcome; Vitamin E; Xenograft Model Antitumor Assays