Symposia of the Society for Experimental Biology 12 , — Flinta, C. Sequence determinants of N-terminal protein processing. European Journal of Biochemistry , — Grunberger, D. Codon recognition by enzymatically mischarged valine transfer ribonucleic acid.
Science , — doi Kozak, M. Point mutations close to the AUG initiator codon affect the efficiency of translation of rat preproinsulin in vivo. Nature , — doi Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes. Cell 44 , — An analysis of 5'-noncoding sequences from vertebrate messenger RNAs.
Nucleic Acids Research 15 , — Shine, J. Determinant of cistron specificity in bacterial ribosomes. Nature , 34—38 doi Restriction Enzymes. Genetic Mutation. Functions and Utility of Alu Jumping Genes. Transposons: The Jumping Genes. DNA Transcription. What is a Gene? Colinearity and Transcription Units. Copy Number Variation. Copy Number Variation and Genetic Disease. Copy Number Variation and Human Disease. Tandem Repeats and Morphological Variation.
Chemical Structure of RNA. Eukaryotic Genome Complexity. RNA Functions. Citation: Clancy, S. Nature Education 1 1 How does the cell convert DNA into working proteins? The process of translation can be seen as the decoding of instructions for making proteins, involving mRNA in transcription as well as tRNA. Aa Aa Aa. Figure Detail. Where Translation Occurs.
Figure 3: A DNA transcription unit. A DNA transcription unit is composed, from its 3' to 5' end, of an RNA-coding region pink rectangle flanked by a promoter region green rectangle and a terminator region black rectangle. Genetics: A Conceptual Approach , 2nd ed. With more than unique interaction partners in the cells, this family of proteins will continue to spark the curiosity of researchers for a long time. Triptolide Figure 3 is a diterpene triepoxide produced by thunder god vine, a plant regularly used in Chinese traditional medicine for rheumatoid arthritis Su et al.
In addition to inhibiting heat shock protein 70, it is an inhibitor of Pol I and Pol II which functions by blocking the transcription elongation process while binding to transcription factor TFIIH Titov et al.
Triptolide kills colorectal cancer cells in vitro and inhibits the growth of colorectal xenografts in a mouse model Wang et al.
Recently, Liang et al. The inhibition of cancer growth both in vitro and in vivo makes triptolide a potential drug candidate for colorectal cancer. However, due to the toxicity of triptolide, only the prodrug disodium salt form of it, minnelide is being studied in human trials for pancreatic and liver cancers Banerjee and Saluja, This process can be disturbed by mimetics of adenosine or fludarabine Figure 4. Figure 4. Chemical structure of the nucleoside analogs that function as premature transcription chain terminators.
Since transcription generally terminates when a poly-A chain is added to the mRNA transcript, modified adenosine analogs have been the focus of research as premature transcription chain terminators. Interestingly, these compounds are not cytotoxic for non-transformed cells Balakrishnan et al. Recently, 8-Cl-Ado showed a positive synergistic effect with another cancer drug in a mice xenograft model of acute myeloid leukemia Buettner et al. Fludarabine Figure 4 is a nucleoside analog which is used in the treatment of different leukemias and lymphomas Gandhi and Plunkett, It was approved in by the FDA and it can be used either alone or in combination with other chemotherapeutics, such as cytarabine or mitoxantrone.
In addition to these, fludarabine can incorporate into RNA and inhibit the transcription process Huang et al. The cytotoxic mechanism of fludarabine seems to be dependent on the cell type, and even a potassium channel was identified to be inhibited by it Huang et al. Since , palbociclib, ribociclib, and abemaciclib have been approved for the treatment of hormone receptor positive breast cancer. CDKs regulate the cell cycle by preventing the phosphorylation of transcription factors.
In cancer their activity is many times distorted to ensure the proliferative state of the cancer cells. Since different CDKs control different parts of the cell cycle, it is beneficial to target them selectively instead of using pan-CDK inhibitors, such as alvocidib.
The main issue in CDK inhibitors is the poor predictability of the patients response, that is if patients benefit from CDK inhibition and with what combination of other drugs Asghar et al. Another issue is that they cannot be used in combination with many cytotoxic drugs or radiotherapy, since these act by stopping the cell cycle, whereas CDK inhibition therapies only work for cycling cells.
It was the first CDK inhibitor which reached clinical trials in Senderowicz, ; Kelland, Since then more than 60 phase I and phase II clinical trials in various cancers have been conducted using it Asghar et al. The broad target spectrum lead to promising in vitro results, but unfortunately the clinical tests showed only a little activity Asghar et al. There are few positive results for leukemia and lymphoma, and new phase I and II clinical trials are continuously started for alvocidib Byrd et al.
Despite all the investments and thorough studies, alvocidib has not made it into phase III clinical trials, as of The main issues with alvocidib and other non-selective CDK inhibitors are the uncertainty of their mechanism of action, the problems in patient selection for clinical trials and the lack of a therapeutic window as a result of CDK inhibition in healthy cells Asghar et al.
Palbociclib Figure 5 is a selective inhibitor of CDK4 and CDK6 and it was the first inhibitor of CDKs that was approved as a cancer therapy in combination with letrozole, an aromatase inhibitor Lu, ; Turner et al. This results in lower levels of cyclins, nucleotide biosynthesis, DNA replication machinery and mitotic regulatory genes Dean et al.
During the extensive clinical trials of palbociclib, its cytotoxic effect have been proven, and the main adverse effect has been neutropenia Asghar et al.
Neutropenia is a common adverse effect of chemotherapies, but in the case of palbociclib it is a rapidly reversible condition which can be avoided by intermittent dosage. The clinical tests also revealed that palbociclib has a beneficial effect in combination with hormone therapy in estrogen receptor ER positive breast cancer cell lines Finn et al. This lead to many phase II studies which confirmed the significant improvement in the median progression-free survival and granted palbociclib the Breakthrough Therapy designated from the FDA in Asghar et al.
It showed similar efficacy to palbociclib with a similar toxicity profile, with the addition of higher hepatotoxicity and rare cardiac QT time prolongation effects Hortobagyi et al. Interestingly, whereas palbociclib is generally used for advanced states of cancer, ribociclib has also shown a positive effect in high-risk early-stage ER positive breast cancer Prat et al. Abemaciclib Figure 5 was developed around the same time as palbociclib, and it gained FDA approval in Even though abemaciclib has similar mechanism of action and usage in cancer treatment for ER positive cancers as palbociclib and ribociclib, the main adverse effects of it are gastro-intestinal issues instead of neutropenia Chen et al.
Translation is the process of polypeptide chain production according to the mRNA template Figure 6. It includes dozens of druggable protein targets and consists of four stages: 1 translation initiation, 2 translation elongation, 3 translation termination and 4 recycling of the translation machinery Roux and Topisirovic, ; Schuller and Green, Figure 6.
A simplified overview of the four stages of translation and where the inhibitors are targeting. The initiation phase is assisted by a wide variety of eukaryotic translation initiation factors eIFs. During the elongation phase, the 80S ribosome moves along the mRNA template, binding new tRNA molecules with corresponding amino acids to synthesize the polypeptide chain. This process is coordinated by the eukaryotic elongation factors eEFs. Once the 80S ribosome encounters a termination codon which is recognized by eukaryotic peptide chain release factors eRFs , it releases from the mRNA and the polypeptide chain.
Finally, the 80S ribosome complex separates into subunits 40 and 60S to begin a new round of translation. At the translation level, it has been shown that many signaling pathways are dysregulated in cancers Wolfe et al.
This association has been bringing translational control into the foreground of targeted cancer therapies Vogel and Marcotte, , where the spotlight was previously reserved for transcription level inhibitors. Here, the first step, initiation, is the most targeted by inhibitors, with the mammalian target of rapamycin mTOR inhibitors being in recent years one of the main targets of study Figure 6 Hua et al.
On the second step of translation, tRNA is targeted for inhibition, thus blocking the protein synthesis process. These inhibitors act by binding the free ribosome, interfering with the normal tRNA binding and thus blocking the elongation step Figure 6 Gandhi et al. The readers interested in a more detailed overview of mTOR and its biology are referred to the recent and comprehensive review written by Kim and Guan, The inhibitors of mTOR complexes can be divided into three generations, first of which consist of rapamycin and its analogs termed rapalogs, which affect only specific parts of the mTOR complexes Kim and Guan, ; Tian et al.
The newest additions to the mTOR related drugs are called RapaLinks which consist of rapamycin linked with an mTOR kinase inhibitor, a combination of the previous two generations. Structurally, rapamycin resembles the immunosuppressant tacrolimus, and it has similar immunosuppressive effect and mechanism of action via the inhibition of T- and B-cells Sehgal, Because of these immunosuppressive properties rapamycin is one of approved drugs for the prophylaxis of renal transplantation Pidala et al.
It was later discovered that in addition to its antifungal and immunosuppressive properties, it is a potent inhibitor of many mammalian kinases Chung et al. About 20 years after the discovery of rapamycin, its target was identified and aptly named, the mammalian target of rapamycin, mTOR Sabers et al. Long-term rapamycin treatment can also affect mTORC2 signaling but the mechanism of this is not clear Kim and Guan, Since mTORC1 complex is activated in numerous human cancers to keep the cancer cells proliferative and increase their nutrient uptake and energy metabolism, rapamycin impairs cancer metabolism and it has been thoroughly studied as a cancer drug Li et al.
However, the unmodified rapamycin has poor water solubility which leads to pharmacokinetic issues and facilitated the development of multiple analogs called rapalogs, the first generation mTOR inhibitors. Figure 7. Selected chemical structures of inhibitors that target the mTOR complexes. Top contains the rapamycin, and its water-soluble analogs, rapalogs. In the middle there are some of the second generation of mTORC inhibitors which target the kinase activity.
On the bottom, one of the third generation mTOR inhibitors is shown, which connects rapamycin scaffold with a second-generation kinase inhibitor. Two water-soluble derivatives of rapamycin, temsirolimus, and everolimus Figure 7 , have been approved for the treatment of renal cancer carcinoma Li et al.
Everolimus is also approved for the treatment of progressive neuroendocrine tumors of pancreatic origin, and refractory mantle cell lymphoma in the EU. Even though many water soluble rapalogs were tested in cell and animal models, their effect in the clinic is generally only modest or weak Kim and Guan, In some cases, these effects can be countered by combining rapalogs with an autophagy inhibitor hydroxychloroquine Rangwala et al.
Later, Torin2 was characterized and tested alone and in combination with other kinase inhibitors against various cancer cell lines Liu et al. The mTOR kinase inhibitors display stronger inhibition of cancer cell proliferation than rapamycin due to their increased efficacy toward mTORC2. However, since mTOR signaling is essential for cell viability, blocking both mTOR complexes causes mTOR kinase inhibitors to have more severe side effects than rapamycin or rapalogs Xie et al.
One such compound is wortmannin, a toxic steroidal furan produced by fungi Brian et al. It is, however, toxic and instable in biological solutions which prevent its usage as a drug. It has been tested in mouse xenograft models of glioma Fan et al. In addition to having activity against many cancer cell lines, RapaLinks are effective against cancerous cells that are resistant to first or second generation mTOR inhibitors Rodrik-Outmezguine et al.
MLN by itself is not very effective in vivo due to its short residence time and its usage is limited by toxicity Graham et al. Even though RapaLinks are large and contain a poorly water-soluble rapamycin, they can pass the blood-brain barrier and their efficacy has been shown in animal models of glioblastoma Fan et al.
If the in vivo results imply anything about clinical usability, we expect to see RapaLinks in clinical trials within the next few years. Silvestrol Figure 8 is a rocaglate derivative that can be isolated from the fruits and twigs of Aglaia foveolate Pan et al. It is cytotoxic toward multiple cancer cell lines in vitro and it displays similar potency to paclitaxel or camptothecin Hwang et al. Silvestrol inhibits the translation initiation by binding to the initiation factor eIF-4A which prevents the ribosome loading onto the mRNA template Cencic et al.
This kills cells by inducing early autophagy and caspase-mediated apoptosis Chen et al. Silvestrol exhibits cytotoxic effects against different human cancer cell lines, such as melanoma, acute myelogenous leukemia, cervical cancer and oral carcinoma Hwang et al.
Even though silvestrol is effectively cytotoxic against multiple cancer cell lines in vitro , only partial protein synthesis inhibition was observed in mice models of lymphoma Bordeleau et al. The main issue with silvestrol and its analogs is that they upregulate multi-drug-resistant gene ABCB1 and that they are substrates of p-glycoprotein, a well-known resistance-causing efflux transporter Gupta et al.
Despite the decade long research, silvestrol and its analogs remain at the preclinical drug research stage, and none of them has made it into clinical trials Peters et al. Omacetaxine, formerly known as homoharringtone Figure 8 , is a plant alkaloid from Cephalotoxus fortune.
It was identified in s as the inhibitor of the initial elongation step of translation Huang, ; Fresno et al.
Because omacetaxine affects the elongation step, it is a more general translation inhibitor than other molecules that target translation initiation which inhibit only the translation of specific sequences Wetzler and Segal, Treatment with omacetaxine leads to a rapid decrease in the number of proteins with short half-lives, including the oncogenic cyclin D1 and c-Myc Robert et al. Omacetaxine was intensely studied after its discovery both in vitro and in vivo against chronic myeloid leukemia but after the approval of imatinib and other tyrosine kinase inhibitors, the scientific interest toward it dwindled Wetzler and Segal, Recently, new clinical studies around omacetaxine have been started due to its synergistic effect with tyrosine kinase inhibitors, especially in the treatment of cancers with mutations in the tyrosine kinase genes Marin et al.
Omacetaxine is approved by the FDA for the treatment of chronic myeloid leukemia if the disease does not respond to two or more tyrosine kinase inhibitors Cortes et al. This way, omacetaxine can help patients who suffer from lack of effect of those drugs, intolerance or drug-drug interactions. The most common adverse effects of omacetaxine are myelosuppression and thrombocytopenia which are observed in almost all patients but they can be managed with supportive care, dose delays and reduction in the number of days that omacetaxine is administered Rosshandler et al.
In the cell, these oligonucleotides can hybridize to target RNA sequences, including mRNA and non-coding nc RNA to inhibit their expression and thereby regulate the availability of specific proteins. Different chemical modifications of synthesized oligonucleotides have been made to increase their nuclease stability, decrease non-specific effects and to improve their cellular uptake Karaki et al. In addition to increased stability, some of these modifications have also enabled the oligomer binding to double-stranded DNA and have altered mechanisms of action.
ASOs have different mechanisms of actions including enzyme-mediated target RNA degradation, steric-hindrance of translation, as well as modulation of splicing and transcription MacLeod and Crooke, This is efficiently mediated by the ubiquitous RNase H and has the advantage that the oligonucleotide can be targeted to any part of the RNA molecule. However, problems of specificity due to activation following partial hybridization have been observed and pose a concern.
Modified oligomers deviate from RNase H-induced cleavage and can inhibit protein expression via other mRNA quality control decay pathways. These include the non-sense-mediated decay NMD Ward et al. Interestingly, this can be used either to block mature protein expression or to correct aberrant splicing thereby restoring the protein function. Furthermore, oligonucleotides can result in steric hindrance of translation by preventing ribosome binding when targeted near the translation initiation codon Chery, ; Goyal and Narayanaswami, In recent years with the growing identification and appreciation of the role of non-coding RNAs in transcription and gene regulation, ASO targeting non-coding RNAs have now also been implicated in modulation of transcription.
It is likely, that new effects on transcription will be identified with increasing use of ASOs in the non-coding RNA field and better understanding of their functions. The power of ASOs as therapeutic agents has long been realized with FDA approval of the first ASO already in and 5 approved to date for nervous muscular or familial metabolic diseases Stein and Castanotto, ; Yamakawa et al. However, antisense therapy for cancer treatment has lagged behind and to date there are no approved ASO therapeutic for cancer.
Nevertheless, there are many ongoing clinical trials using ASOs targeting primarily cell proliferation and signaling as well as cancer stroma and resistance to chemotherapy. With these encouraging results a multicenter phase III trial was initiated, however it was discontinued due to patient recruitment failure NCT AP has also been tested for the treatment of patients with advanced pancreatic carcinoma, metastasizing melanoma, or metastatic colorectal carcinoma and a phase II trial demonstrated encouraging survival results Stauder et al.
In addition, cellular trafficking and localization of AZD across different tumor cell lines have been characterized and was found to vary Linnane et al. Following completion of a phase I trial the molecule was demonstrated to be safe and well-tolerated, but it was discontinued by AstraZeneca because of its insufficient efficacy possibly due to targeting both mutant and wild-type KRAS mRNA Yang et al.
The partial base pairing compromises the AGO slicer catalytic activity and instead results in either translation repression or degradation of mRNA. Activation of RNAi and the use of siRNA for therapeutic means have the appeal of small molecules but have the added value of specificity and the flexibility of target selection.
For these reasons some siRNA molecules were already in clinical trials within 10 years of their discovery. However, early clinical trials with siRNAs failed, some of which due to non-specific activation of the innate immunity. For a comprehensive review see Khvorova and Watts, These modifications not only served to increase safety by avoiding dsRNA activation of the immune response, but they also increased the potency and stability of dsRNA by increasing their resistance to endonucleases, as well as in some instances facilitating antisense strand selectivity Zuckerman and Davis, In addition to chemical modifications of dsRNA, progress in targeting and packaging of these for improved delivery of RNAi drugs was also necessary Pecot et al.
Successful packaging of dsRNA was achieved in nanoparticles, polymers and dendrimers to name a few, and targeting has been accomplished with aptamers, antibodies, peptides and small molecules Zhou and Rossi, ; Springer and Dowdy, In cases where antagonism of the miRNA is desired a synthetic, single-stranded RNA is introduced to target the miRNA for degradation and thereby inhibit its activity and disease progression.
Both of these strategies can be useful for cancer treatment, either in inhibiting oncogenes or gene products facilitating cancer growth or to reactivate miRNAs that are downregulated in tumors Van Roosbroeck and Calin, ; Takahashi et al. RNA therapeutic avenues are likely to extend in the future, as we are not limited to RNAi mechanisms in the cytoplasm but dsRNAs can also act in the nucleus to cause transcriptional gene silencing TGS via modification of epigenetic marks Castel and Martienssen, ; Martienssen and Moazed, In addition, siRNA targeting gene promoters can also cause transcriptional activation Laham-Karam et al.
Today, many RNAi drugs for cancer therapy are in clinical trials. LODER is a polymeric matrix of poly lactic-co-glycolic acid that facilitates prolonged delivery of siRNA and has been tested for the treatment of pancreatic cancer. Following preclinical safety and toxicity assessment Ramot et al.
The RNAi drug was found to be safe and well-tolerated despite some adverse reactions and importantly demonstrated anticancer effects. It has now proceeded to Phase II trials. EphA2 is a tyrosine kinase receptor that normally functions in neuronal development but its overexpression has been observed in human cancers and decreased expression can reduce tumorigenicity Ieguchi and Maru, Both prodrugs of it and mimics have been tested for cancer treatment Zhao et al.
Although miRNA targeted therapy remains appealing the feasibility of such therapy is still to be proven. Although different chemical modification of synthetic RNA molecules intended for RNAi therapeutics have increased stability and demonstrated favorable pharmacokinetics properties, these Chemo-engineered RNAs are different from naturally transcribed RNA molecules in living cells, which are largely unmodified.
This difference affects the structure, properties, and possibly the activity and immunogenicity of these molecules reviewed in Yu et al. Also, effort has been made to bioengineer RNA molecules in living cells, including in bacteria and yeast Huang et al. Importantly, the BERAs produced have demonstrated biological activity in cells and in animal models. Examples of these tested for tumor treatment, are miRa prodrugs.
Likewise, systemic delivery of an improved miRa-5p prodrug significantly decreased metastatic lung xenograft tumor growth in mice Ho et al. In addition, other formulation of miRa prodrugs have resulted in similar findings in orthotopic osteosarcoma xenograft tumor mouse model Zhao et al.
In both these studies, it was also shown that the therapeutic doses of mira prodrug were well-tolerated as indicated in blood chemistry profiles monitoring for hepatic and renal toxicities. Recently, another miRNA prodrug was investigated targeting pancreatic cancer Li et al.
A bioengineered miR was tested alone or in combination with chemotherapy treatment in PANC-1 xenograft and pancreatic cancer patients derived xenograft PDX mouse models and was found to be effective in reducing tumor growth and was well-tolerated Tu et al. This can be done by cationic lipids, polymers, and peptides Kim et al. Specifically, polyethylenimine PEI -based polyplexes complexes of nucleotides and polycations have facilitated efficient delivery in tumor models Zhao et al.
However due to potential toxicity of polyplexes Lv et al. Increased serum stability of these BERAs as well as improved delivery, therapeutic effectiveness and survival of tumor bearing mice were observed. These positive results encourage the further development of BERA for tumor therapy.
Oncogenes are genes that can cause cancer once mutated or when expressed at high levels Croce, Many oncogenic pathways lead to altered transcription or translation of various proteins. In order to keep the topic of this review we will focus on two oncogenic targets that are involved with transcription and translation; transcription factors and KRAS. Both of these oncogenes were previously thought to be undruggable but nevertheless, a few inhibitors for both of them have been published in the last few years.
The readers interested in the drugs designed for oncogenic kinases or other oncogenic pathways are referred to other reviews Bhullar et al. The idea of targeting transcription factors in cancer has been around about 20 years Darnell, Transcription factors can drive oncogenesis as fusion proteins or by chromosomal translocation events Bushweller, The DNA binding site of transcription factors with its positively charged environment is a difficult target for developing small-molecule inhibitors, and thus most of the recent efforts have been aimed for the protein-protein interaction PPI inhibition, such as RG Arkin et al.
Transcription factors can be directly targeted by disrupting their transcription or translation, stabilizing their auto-inhibitory states, inducing covalent modifications with cysteine bridges or changing their post-translational modifications Bushweller, Here we will shortly present the most advanced molecules that target transcription factors and are in or close to starting clinical trials Figure 9. More detailed insights of targeting transcription factors in cancer can be found in the excellent review by Bushweller, Figure 9.
Molecules that target transcription factors and are in clinical trials or close to starting them. So far, four different PPI inhibitors that target transcription factors have made it into the clinical trials or are very close to starting them Bushweller, Two of these, RG idasanutlin and HDM siremadlin; Figure 9 , prevent MDM2 binding to p53 which prevents the degradation of p53 and increases its cellular levels leading to increased cell death Ding et al.
RG and HDM have multiple phase I clinical trials ongoing both against solid tumors such as melanoma as well as hematological malignancies such as leukemia.
The clinical trials in leukemia are planned for KO and SNDX which target the mixed lineage leukemia MLL transcription factor and inhibit its binding to menin which prevents this fusion protein from activating genes driving leukemia. Unfortunately, the structures of these inhibitors have not been made public yet. The inhibition with SY leads to decreased levels of multiple oncogenic transcription factors and it exhibits the inhibitory effects on multiple cancer cell lines at nanomolar level.
In addition, mouse xenograft studies showed modest antitumor activity in both AML as well as ovarian cancer, and a synergistic effect with venetoclax Hu et al. Both inhibitors lower the expression levels of the c-Myc oncogene and the proliferation rates of multiple cancer cell lines, and in animal models they display suitable properties for oral dosing in humans.
The clinical trials are ongoing for advanced cancers, both solid tumors and leukemias. Drugs affecting transcription and translation are difficult to develop. As RAS proteins are the most commonly mutated proteins in cancer and at the same time are part of the signaling cascade from the EGFR receptor, these have been a natural target for drug discovery.
Those interested to know more about RAS protein structure and function are advised to look at recently published review Pantsar, and another review about early drug discovery work on RAS by Ostrem and Shokat As there are no other clear druggable pockets in RAS direct targeting seemed to be an impossible mission. The problem was partially solved by the seminal work of Shokat lab which demonstrated that covalent interaction targeting mutated G12C residues is able to deliver in vivo relevant inhibition of RAS activation Ostrem et al.
The initial compounds presented were developed by disulphide-fragment based screening using tethering compounds. After early hit-optimization guided by X-ray crystallography an optimized G12C targeting covalent inhibitor was presented.
In the optimized compounds disulfides were replaced by different electrophilic warheads and especially acrylamides were used. Upon covalent interaction G12C position compounds were binding previously unknown allosteric pocket. This is not surprising as such, but more surprising is a very recent report concerning the rapid non-uniform adaptation to KRAS G12C inhibition Xue et al.
According to Xue et al. Partially this effect might be specific for the currently used G12C inhibitor ARS but due to similar binding mode as with AMG it seems that this conclusion will be a general one Janes et al. History has shown us that it is indeed not straight-forward to develop transcription or translation inhibitors.
Even more difficult is to target these inhibitors only toward malignant cells. There have been a few clinical successes in their development, such as the CDK inhibitors, especially in combination with other chemotherapeutics.
Targeting these central cellular processes has advantages to be more directed to cancer cells than non-specific chemotherapeutic agents such as cisplatin. On the side of disadvantages, targeting transcription and translation may affect multiple pathways hence circumventing the targeted pathway, and there are inevitable side effects arising from the fact that all cells require transcription and translation for their proper function.
Transcription and translation are fundamental processes that targeting them is bound to result in cell death, as such cancer treatment based on these processes needs to be done in a manner that is safe for healthy cells.
To achieve the specific and effective treatment, the myriad of proteins involved will continue to offer drug design possibilities far into the future. In addition, RNA was previously considered to be undruggable and not suitable as a drug itself, but now RNA-targeting and RNA-based drugs can be used as very precise methods to target some cancers.
The recently discovered RNA activation of transcription offers uncharted possibilities in the treatment of cancer. Furthermore, transcription factors and oncogenes were also thought to be undruggable, but within the last few years we have seen some molecules targeting them entering clinical trials.
By widening the scope of drug targets from traditional proteins with specified binding sites to transcription factors, oncogenes and RNA molecules, we are discovering new and specific ways to target cancer cells. So far, we have produced some highly specific, safe and efficacious cancer therapies which inhibit transcription and translation, and the newly discovered targets and our ever-increasing knowledge about the biological basics of these processes is bound to keep this field of inhibitor development ongoing far into the future.
All authors contributed to manuscript revision, read and approved the submitted version. The authors thank Maire Taponen Foundation NL-K personal grant and competitive funding to strengthen university research profiles, 5th call, funding to University of Eastern Finland, funded by the Academy of Finland, funding decision The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors apologize for colleagues whose work could not be referenced due to word count limits. Abdelrahim, M. TAS preclinical, clinical and beyond. Oncology 85, — Alqahtani, A. Bromodomain and extra-terminal motif inhibitors: a review of preclinical and clinical advances in cancer therapy.
Future Sci. Arkin, M. Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. Arruebo, M. Assessment of the evolution of cancer treatment therapies. Cancers 3, — Asghar, U. Biology and the Scientific Method. BIO - Cell Structure.
Here is the third BIO lecture from May 08, Again, I'd appreciate comments on the correctness as well as suggestions for improvement.
DNA is a long double-stranded molecule residing inside the nucleus of every cell. It is usually tightly coiled forming chromosomes in which it is protected by proteins. Each of the two strands of the DNA molecule is a chain of smaller molecules.
Each link in the chain is composed of one sugar molecule, one phosphate molecule and one nucleotide molecule. The two strands of DNA are structured in such a way that an adenine on one strand is always attached to a thymine on the other strand, and the guanine of one strand is always bound to cytosine on the other strand.
Thus, the two strands of the DNA molecule are mirror-images of each other. The exact sequence of nucleotides of all of the DNA on all the chromosomes is the genome.
Each cell in the body has exactly the same chromosomes and exactly the same genome with some exceptions we will cover later. A gene is a small portion of the genome - a sequence of nucleotides that is expressed together and codes for a single protein polypeptide molecule. Cell uses the genes to synthesize proteins. This is a two-step process. The first step is transcription in which the sequence of one gene is replicated in an RNA molecule.
The second step is translation in which the RNA molecule serves as a code for the formation of an amino-acid chain a polypeptide.
For a gene to be expressed, i. Instead of thymine, RNA has uracil U. Once the whole gene s to 10,s of bases in a row is transcribed, the RNA molecule detaches. The RNA called messenger RNA or mRNA may be further modified by addition of more A bases at its tail, by addition of other small molecules to some of the nucleotides and by excision of some portions introns out of the chain.
The removal of introns the non-coding regions and putting together the remaining segments - exons - into a single chain again, is called RNA splicing. RNA splicing allows for one gene to code for multiple related kinds of proteins, as alternative patterns of splicing may be controlled by various factors in the cell.
It enters the endoplasmatic reticulum and attaches itself to one of the membranes in the rough ER. Other types of RNA also exist but are not as well understood, although they appear to play regulatory roles in gene expression and also be involved in protection against invading viruses. Some mRNA molecules are abundant, numbering in the hundreds or thousands, as is often true of transcripts encoding structural proteins.
Other mRNAs are quite rare, with perhaps only a single copy present, as is sometimes the case for transcripts that encode signaling proteins. In eukaryotes, transcripts for structural proteins may remain intact for over ten hours, whereas transcripts for signaling proteins may be degraded in less than ten minutes. Cells can be characterized by the spectrum of mRNA molecules present within them; this spectrum is called the transcriptome.
Whereas each cell in a multicellular organism carries the same DNA or genome, its transcriptome varies widely according to cell type and function. For instance, the insulin-producing cells of the pancreas contain transcripts for insulin, but bone cells do not. Even though bone cells carry the gene for insulin, this gene is not transcribed. Therefore, the transcriptome functions as a kind of catalog of all of the genes that are being expressed in a cell at a particular point in time.
Figure 5: An electron micrograph of a prokaryote Escherichia coli , showing DNA and ribosomes This Escherichia coli cell has been treated with chemicals and sectioned so its DNA and ribosomes are clearly visible. The DNA appears as swirls in the center of the cell, and the ribosomes appear as dark particles at the cell periphery. Courtesy of Dr. Abraham Minsky Ribosomes are the sites in a cell in which protein synthesis takes place. Cells have many ribosomes, and the exact number depends on how active a particular cell is in synthesizing proteins.
For example, rapidly growing cells usually have a large number of ribosomes Figure 5. Ribosomes are complexes of rRNA molecules and proteins, and they can be observed in electron micrographs of cells. Sometimes, ribosomes are visible as clusters, called polyribosomes. In eukaryotes but not in prokaryotes , some of the ribosomes are attached to internal membranes, where they synthesize the proteins that will later reside in those membranes, or are destined for secretion Figure 6.
Although only a few rRNA molecules are present in each ribosome, these molecules make up about half of the ribosomal mass. The remaining mass consists of a number of proteins — nearly 60 in prokaryotic cells and over 80 in eukaryotic cells.
Within the ribosome, the rRNA molecules direct the catalytic steps of protein synthesis — the stitching together of amino acids to make a protein molecule. Eukaryotic and prokaryotic ribosomes are different from each other as a result of divergent evolution. These differences are exploited by antibiotics, which are designed to inhibit the prokaryotic ribosomes of infectious bacteria without affecting eukaryotic ribosomes, thereby not interfering with the cells of the sick host.
Figure 6: The endoplasmic reticulum of this eukaryotic cell is studded with ribosomes. Electron micrograph of a pancreatic exocrine cell section. The cytosol is filled with closely packed sheets of endoplasmic reticulum membrane studded with ribosomes. At the bottom left is a portion of the nucleus and its nuclear envelope. Image courtesy of Prof.
Orci University of Geneva, Switzerland. Merging cultures in the study of membrane traffic. Nature Cell Biology 6 , doi
0コメント