3-hydroxy-4-3--4--5--tetramethoxychalcone and Lung-Neoplasms

Drug resistance is a major hurdle in anticancer chemotherapy. Combined therapy using drugs with distinct mechanisms of function may increase anticancer efficacy. We have recently identified the novel chalcone derivative, chalcone-24 (Chal-24), as a potential therapeutic that kills cancer cells through activation of an autophagy-mediated necroptosis pathway. In this report, we investigated if Chal-24 can be combined with the frontline genotoxic anticancer drug, cisplatin for cancer therapy. The combination of Chal-24 and cisplatin synergistically induced apoptotic cytotoxicity in lung cancer cell lines, which was dependent on Chal-24-induced autophagy. While cisplatin slightly potentiated the JNK/Bcl2/Beclin1 pathway for autophagy activation, its combination with Chal-24 strongly triggered proteasomal degradation of the cellular inhibitor of apoptosis proteins (c-IAPs) and formation of the Ripoptosome complex that contains RIP1, FADD and caspase 8. Furthermore, the cisplatin and Chal-24 combination induced dramatic degradation of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein large (cFLIPL) which suppresses Ripoptosome-mediated apoptosis activation. These results establish a novel mechanism for potentiation of anticancer activity with the combination of Chal-24 and cisplatin: to enhance apoptosis signaling through Ripoptosome formation and to release the apoptosis brake through c-FLIPL degradation. Altogether, our work suggests that the combination of Chal-24 and cisplatin could be employed to improve chemotherapy efficacy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Autophagy; CASP8 and FADD-Like Apoptosis Regulating Protein; Cell Line, Tumor; Chalcones; Cisplatin; Drug Resistance, Neoplasm; Drug Synergism; Humans; Inhibitor of Apoptosis Proteins; Lung Neoplasms; MAP Kinase Signaling System; Phosphorylation; Proto-Oncogene Proteins c-bcl-2

We are interested in investigating the biological activity of chalcones, a major class of compounds found in the beverage kava, in order to develop potent and selective chemopreventive candidates. Consumption of kava in the South Pacific Islands is inversely correlated with cancer incidence, even among smokers. Accordingly, chalcones have anti-cancer activities in animal and cell culture models. To investigate signaling pathways that affect chalcone action we studied a potent analog, (E)-3-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (chalcone-24). Chalcone-24 was selected from a series of chalcone analogs that were synthesized based on the structures derived from flavokawain compounds found in kava, and screened in A549 lung cancer cells for induction of cytotoxicity and inhibition of NF-κB, a transcription factor associated with cell survival. Incubation of A549 cells with chalcone-24 resulted in a dose-dependent inhibition of cell viability, inhibition of NF-κB, activation of caspases, and activation of extracellular signal regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK); ERK1/2 and JNK are mitogen activated protein kinases that play central roles in regulating cell fate. Pharmacological inhibitors of ERK1/2 or JNK increased the sensitivity of A549 cells to chalcone-24-induced cytotoxicity, without affecting NF-κB or caspase activity. These results will help refine the synthesis of chalcone analogs to maximize the combination of actions required to prevent and treat cancer.

Topics: Cell Survival; Chalcone; Chalcones; Drug Resistance, Neoplasm; Humans; Kava; Lung Neoplasms; MAP Kinase Kinase 4; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Neoplasms

Chalcone is a privileged structure, demonstrating promising anti-inflammatory and anticancer activities. One potential mechanism is to suppress nuclear factor kappa B (NF-kappaB) activation. The structures of chalcone-based NF-kappaB inhibitors vary significantly that there is minimum information about their structure-activity relationships (SAR). This study aims to establish SAR of chalcone-based compounds to NF-kappaB inhibition, to explore the feasibility of developing simple chalcone-based potent NF-kappaB inhibitors, and to evaluate their anticancer activities. Three series of chalcones were synthesized in one to three steps with the key step being aldol condensation. These candidates demonstrated a wide range of NF-kappaB inhibitory activities, some of low micromolar potency, establishing that structural complexity is not required for NF-kappaB inhibition. Lead compounds also demonstrate potent cytotoxicity against lung cancer cells. Their cytotoxicities correlate moderately well with their NF-kappaB inhibitory activities, suggesting that suppressing NF-kappaB activation is likely responsible for at least some of the cytotoxicities. One lead compound effectively inhibits lung tumor growth with no signs of adverse side effects.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Chalcone; Chalcones; Female; Genes, Reporter; Humans; I-kappa B Kinase; Inhibitory Concentration 50; Interleukin-1 Receptor-Associated Kinases; Luciferases; Lung Neoplasms; Mice; Mice, Nude; NF-kappa B; Structure-Activity Relationship; Tumor Necrosis Factor-alpha