rottlerin and Neoplasms

ATPases Associated with Diverse Cellular Activity (AAA ATPase) are essential enzymes found in all organisms. They are involved in various processes such as DNA replication, protein degradation, membrane fusion, microtubule serving, peroxisome biogenesis, signal transduction, and the regulation of gene expression. Due to the importance of AAA ATPases, several researchers identified and developed small-molecule inhibitors against these enzymes. We discuss six AAA ATPases that are potential drug targets and have well-developed inhibitors. We compare available structures that suggest significant differences of the ATP binding pockets among the AAA ATPases with or without ligand. The distances from ADP to the His20 in the His-Ser-His motif and the Arg finger (Arg353 or Arg378) in both RUVBL1/2 complex structures bound with or without ADP have significant differences, suggesting dramatically different interactions of the binding site with ADP. Taken together, the inhibitors of six well-studied AAA ATPases and their structural information suggest further development of specific AAA ATPase inhibitors due to difference in their structures. Future chemical biology coupled with proteomic approaches could be employed to develop variant specific, complex specific, and pathway specific inhibitors or activators for AAA ATPase proteins.

Topics: ATPases Associated with Diverse Cellular Activities; Binding Sites; Carbazoles; Humans; Molecular Dynamics Simulation; Neoplasms; Pyrazoles; Pyrimidines; Quinazolines; Small Molecule Libraries; Zearalenone

Human cells possess tightly controlled mechanisms to rescue DNA replication following DNA damage caused by environmental and endogenous carcinogens using a set of low-fidelity translesion synthesis (TLS) DNA polymerases. These polymerases can copy over replication blocking DNA lesions while temporarily leaving them unrepaired, preventing cell death at the expense of increasing mutation rates and contributing to the onset and progression of cancer. In addition, TLS has been implicated as a major cellular mechanism promoting acquired resistance to genotoxic chemotherapy. Owing to its central role in mutagenesis and cell survival after DNA damage, inhibition of the TLS pathway has emerged as a potential target for the development of anticancer agents. This review will recap our current understanding of the structure and regulation of DNA polymerase complexes that mediate TLS and describe how this knowledge is beginning to translate into the development of small molecule TLS inhibitors.

Topics: Animals; Antineoplastic Agents; Cell Survival; DNA Damage; DNA-Directed DNA Polymerase; Dose-Response Relationship, Drug; Humans; Molecular Structure; Neoplasms; Small Molecule Libraries; Structure-Activity Relationship

Recently, a wide range of food-derived phytochemical compounds and their synthetic derivatives have been proposed for cancer treatment. Unfortunately, data available in related literature focus on the anti-cancer properties of compounds derived from edible plants, while very little is known about those derived from non-edible plants. And thus, the underlying mechanisms of their anti-cancer effects are yet to be elucidated. This review collates the available data on the anti-cancer activities of six phytochemical-derived compounds from edible and non-edible plants, i.e. rottlerin, berbamine, sparstolonin B, sulforaphane, plumbagin and 6-shogaol. These compounds are used as bioactive markers for cytotoxicity against tumors. As such, understanding their mode of action will provide the rationale for the combination strategies of these compounds with other drugs in the battle against cancer.

Topics: Acetophenones; Antineoplastic Agents, Phytogenic; Benzopyrans; Benzylisoquinolines; Catechols; Heterocyclic Compounds, 4 or More Rings; Humans; Isothiocyanates; Naphthoquinones; Neoplasms; Phytotherapy; Plant Extracts; Signal Transduction; Sulfoxides

Autophagy, a lysosomal degradation pathway for cellular constituents and organelles, is an adaptive and essential process required for cellular homeostasis. Although autophagy functions as a survival mechanism in response to cellular stressors such as nutrient or growth factor deprivation, it can also lead to a non-apoptotic form of programmed cell death (PCD) called autophagy-induced cell death or autophagy-associated cell death (type II PCD). Current evidence suggests that cell death through autophagy can be induced as an alternative to apoptosis (type I PCD), with therapeutic purpose in cancer cells that are resistant to apoptosis. Thus, modulating autophagy is of great interest in cancer research and therapy. Natural polyphenolic compounds that are present in our diet, such as rottlerin, genistein, quercetin, curcumin, and resveratrol, can trigger type II PCD via various mechanisms through the canonical (Beclin-1 dependent) and non-canonical (Beclin-1 independent) routes of autophagy. The capacity of these compounds to provide a means of cancer cell death that enhances the effects of standard therapies should be taken into consideration for designing novel therapeutic strategies. This review focuses on the autophagy- and cell death-inducing effects of these polyphenolic compounds in cancer.

Topics: Acetophenones; Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Benzopyrans; Cell Line, Tumor; Curcumin; Gene Expression Regulation, Neoplastic; Genistein; Humans; Membrane Proteins; Neoplasms; Polyphenols; Quercetin; Resveratrol; Signal Transduction; Stilbenes

Because cancers are caused by deregulation of hundreds of genes, an ideal anticancer agent should target multiple gene products or signaling pathways simultaneously. Recently, extensive research has addressed the chemotherapeutic potential of plant-derived compounds. Among the ever-increasing list of naturally occurring anticancer agents, Rottlerin appears to have great potentiality for being used in chemotherapy because it affects several cell machineries involved in survival, apoptosis, autophagy, and invasion. The underlying mechanisms that have been described are diverse, and the final, cell-specific, Rottlerin outcome appears to result from a combination of signaling pathways at multiple levels. This paper seeks to summarize the multifocal signal modulatory properties of Rottlerin, which merit to be further exploited for successful prevention and treatment of cancer.

Topics: Acetophenones; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Benzopyrans; Drug Therapy, Combination; Humans; Neoplasms

CYP2C8 is a crucial CYP isoform responsible for the metabolism of xenobiotics and endogenous molecules. CYP2C8 converts arachidonic acid to epoxyeicosatrienoic acids (EETs) that cause cancer progression. Rottlerin possess significant anticancer actions. However, information on its CYP inhibitory action is lacking in the literature and therefore, we aimed to explore the same using in silico, in vitro, and in vivo approaches. Rottlerin showed highly potent and selective CYP2C8 inhibition (IC

Topics: Acetophenones; Animals; Cytochrome P-450 CYP2C8; Cytochrome P-450 Enzyme System; Humans; Microsomes, Liver; Molecular Docking Simulation; Neoplasms; Rats

Cisplatin is a widely used cancer therapy drug that unfortunately has major side effects in normal tissues, notably nephrotoxicity in kidneys. Despite intensive research, the mechanism of cisplatin-induced nephrotoxicity remains unclear, and renoprotective approaches during cisplatin-based chemotherapy are lacking. Here we have identified PKCδ as a critical regulator of cisplatin nephrotoxicity, which can be effectively targeted for renoprotection during chemotherapy. We showed that early during cisplatin nephrotoxicity, Src interacted with, phosphorylated, and activated PKCδ in mouse kidney lysates. After activation, PKCδ regulated MAPKs, but not p53, to induce renal cell apoptosis. Thus, inhibition of PKCδ pharmacologically or genetically attenuated kidney cell apoptosis and tissue damage, preserving renal function during cisplatin treatment. Conversely, inhibition of PKCδ enhanced cisplatin-induced cell death in multiple cancer cell lines and, remarkably, enhanced the chemotherapeutic effects of cisplatin in several xenograft and syngeneic mouse tumor models while protecting kidneys from nephrotoxicity. Together these results demonstrate a role of PKCδ in cisplatin nephrotoxicity and support targeting PKCδ as an effective strategy for renoprotection during cisplatin-based cancer therapy.

Topics: Acetophenones; Animals; Antineoplastic Agents; Apoptosis; Benzopyrans; Cell Line, Tumor; Cisplatin; Enzyme Activation; Enzyme Inhibitors; Humans; Kidney; Kidney Tubules, Proximal; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Mitogen-Activated Protein Kinases; Neoplasm Transplantation; Neoplasms; Protein Kinase C-delta; src-Family Kinases; Tumor Suppressor Protein p53

The acidic leucine-rich nuclear phosphoprotein 32 (ANP32)B has been reported to regulate gene expression by acting as a histone chaperone or modulate messenger RNA trafficking by serving as a HuR ligand. However, its exact cellular functions are poorly understood. By utilizing a proteomics-based approach, in this work, we identify that the human ANP32B protein is cleaved during apoptosis induction by NSC606985, a novel camptothecin analog. Further investigation shows that various apoptosis inducers cause a decrease of full-length ANP32B in multiple cell lines with a concomitant increase of an approximately 17 kDa fragment. The proteolytic cleavage of ANP32B is inhibited by a specific caspase-3 inhibitor Z-DEVD-fmk, and it cannot be seen in NSC606985-induced death of caspase-3-deficient MCF-7 cells. In vitro caspase cleavage assay and mutagenesis experiment reveal that ANP32B is a direct substrate of caspase-3 and it is primarily cleaved at the sequence of Ala-Glu-Val-Asp, after Asp-163. Additionally, the reduced expression of endogenous ANP32B by specific small interfering RNA enhances caspase-3 activation and apoptosis induction by NSC606985 and etoposide. These results suggest that ANP32B is a novel substrate for caspase-3 and acts as a negative regulator for apoptosis, the mechanism of which remains to be explored.

Topics: Acetophenones; Antineoplastic Agents; Apoptosis; Benzopyrans; Camptothecin; Carcinoma; Caspase 3; Cell Line, Tumor; Cysteine Proteinase Inhibitors; Down-Regulation; Enzyme Activation; Female; Humans; Leukemia, Myeloid; Male; Neoplasm Proteins; Neoplasms; Nuclear Proteins; Recombinant Fusion Proteins; RNA Interference; RNA, Small Interfering; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Substrate Specificity

The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.

Topics: Animals; Cell Survival; Cells, Cultured; Mice; Molecular Structure; Neoplasms; Neurons; Pharmaceutical Preparations; Sensitivity and Specificity; Stem Cells