Certain compounds that contain lipid can induce apoptosis and act as tumor-suppressors, because a variety of stress stimuli cause apoptosis by increasing intracellular ceramide to initiate apoptotic signaling. Most current anticancer drugs kill actively dividing cells by the induction of apoptosis (Fulda S, Int J Cancer, 2009, 124, 11-515). In addition to this “classical” cancer chemotherapy, approaches that block molecular pathways involved in tumor cell proliferation and therapies that induce alternative cell death pathways are of interest for drug development (Ricci M S and Zong W X, Oncologist, 2006, 11, 42-357). Apoptotic cell death involves a series of events leading to characteristic changes in cell morphology, including loss of cell membrane asymmetry, nuclear fragmentation, chromatin condensation, chromosomal DNA fragmentation and activation of caspases. Unfortunately, cancer cells often acquire resistance to agents that activate the apoptotic pathway. Therefore, alternative cell death pathways are being examined for exploitation in cancer chemotherapy.
Programmed cell death has been classified based on morphological criteria into several categories (Okada H, Mak T W, Nat Rev Cancer, 2004, 4, 592-603). The most extensively studied is apoptosis, or type I cell death, which is characterized by cell rounding, membrane blebbing, cytoplasmic condensation and fragmentation, nuclear pyknosis, and chromatin condensation/fragmentation. Apoptotic bodies are rapidly phagocytized and digested by macrophages or neighboring cells (Lauber K, et al., Mol Cell, 2004, 14, 277-87). The second type of programmed cell death is autophagy which is rarely investigated, or type II cell death, which is characterized by the appearance of abundant autophagic vacuoles in the cytoplasm, and enlargement of the endoplasmic reticulum and the Golgi apparatus (Cuervo A M. Mol Cell Biochem, 2004, 263, 55-72; and Meijer A J, et al., Int J Biochem Cell Biol, 2004, 36, 2463-72).
The type III cell death is necrosis, which was before regarded as an unregulated and uncontrollable process. Evidence now reveals that necrosis can also occur in a regulated manner. The initiation of programmed necrosis, ‘necroptosis’, by death receptors (such as tumour necrosis factor receptor 1) requires the kinase activity of receptor-interacting protein 1 (RIP1; also known as RIPK1) and RIP3 (also known as RIPK3), and its execution involves the active disintegration of mitochondrial, lysosomal and plasma membranes. Necroptosis participates in the pathogenesis of diseases, including ischaemic injury, neurodegeneration and viral infection, thereby representing an attractive target for the avoidance of unwarranted cell death (Vandenabeele P., et al., Nature Reviews Molecular Cell Biology, 2010, 11, 700-714).
There are a number of cytotoxic agents that are currently being used or studied for the treatment of cancer. One of these, Paclitaxel, (also referred to as TAXOL®) was first identified in 1971 by Wani and collaborators (Wani M C et al. J. Am. Chem, Soc., 1971, 93, 2325-2327) following a screening program of plant extracts of National Cancer Institute. This complex diterpene shows cytotoxic activity against several types of tumors and is presently used in the treatment of some cancers such as ovarian and breast cancers. Clinical studies suggest that TAXOL® could eventually be used in the treatment of over 70% of human cancers.
Paclitaxel differs from other cytotoxic drugs by its unique mechanism of action. It interferes with cell division by manipulating the molecular regulation of the cell cycle. Paclitaxel binds to tubulin, the major structural component of microtubules that are present in all eukaryotic cells. Unlike other antimitotic agents such as vinca alkaloids and colcichine, which inhibit the polymerization of tubulin, paclitaxel promotes this assembly of tubulin and stabilizes the resulting microtubules. This event leads to the interruption of cell division, and ultimately to cell death. The antitumor property of taxoid compounds has also lead to the generation of new anticancer drugs derived from taxanes. Taxortere™ (sold by Rhone-Poulenc Rorer), which is produced from 10-deacetylbaccatin III hemysynthesis, is currently used in the treatment of ovarian and breast cancers. While agents such as TAXOL® and Taxotere have made an advance in the treatment of metastatic ovarian and metastatic breast cancer, the majority of those treated still ultimately succumb to these diseases. No single drug or drug combination is curative for advanced metastatic cancer and patients typically succumb to the cancers in several years. Thus, new drugs or combinations that can prolong onset of life-threatening tumors and/or improve quality of life by further reducing tumor-load are very important. (see U.S. Pat. No. 6,664,288)
Several groups have observed necrosis-like cell death that appears to occur in a caspase independent manner. Furthermore, nonapoptotic cell death appears to provide a compensatory mechanism for cell killing when apoptotic regulators such as caspases and Apaf1 are compromised. Thus, it would be beneficial to determine methods, enzymatic pathways and compounds that induce such nonapoptotic mechanisms to compensate when programmed death by apoptosis is compromised. (see U.S. Pat. No. 7,838,645)
Another interesting discovery was on the ability of small molecules that can cause necrosis in cancer cells but do not affect normal cells. These small molecules like Nutlin-2 can bind to HDM-2 in combination with a membrane resident component like Guanidinylated biphenyl. This formulation can treat cancer by targeting deficient p53 or non-p53 cancer cells and causing membranolysis in a subject having a plurality of cancer cells. (see United States Patent Application Publication Number US2011/0183915A1).
Recently, small molecule diterpenes belonging to xenicane skeleton have been discovered. These molecules induce apoptosis upstream of Bax and Bak in tumor cells. The diterpene affects cell in a manner similar to that of HSP90 and HDAC inhibitors and in a manner opposite of PI3 kinase/mTOR inhibitors. The diterpene also inhibits selectively HDAC6 and represents a new model structure of selective HDAC inhibitors which will contribute to the development of HDAC practical isoform selective. The vast majority of human solid tumors are of epithelial origin, and defects in apoptosis, mostly upstream of Bax and Bak, play important roles in both tumor suppression and mediation of chemotherapeutic response. (see U.S. Pat. No. 8,183,395).
Andrianasolo, E H, et al., Nat. Prod., 2011, 74 (4), 842-846 reported the isolation of two ceramide derivatives, bathymodiolamides A (1) and B (2), from the deep-sea hydrothermal vent invertebrate mussel Bathymodiolus thermophilus. The molecular structures of these compounds were determined using a combination of NMR spectroscopy, mass spectrometry, and chemical degradation. Biological activities were assessed in a ApopScreen cell-based screen for apoptosis induction and potential anticancer activity. The results showed that 1 and 2 inhibit the growth of two cancer cell lines [HeLa (cervical cancer) (IC50 0.4 μM for 1 and IC50 0.5 μM for 2) and MCF7 (breast cancer) (IC50 0.1 μM for 1 and IC50 0.2 μM for 2)].
Currently there is a need for compositions and methods that are useful for treating or preventing cancer.
USPTO Backgrounds
USPTO Backgrounds