Altering phosphorylation in cancer through PP2A modifiers.

Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase integral to the regulation of many cellular processes. Due to the deregulation of PP2A in cancer, many of these processes are turned toward promoting tumor progression. Considerable research has been undertaken to discover molecules capable of modulating PP2A activity in cancer. Because PP2A is capable of immense substrate specificity across many cellular processes, the therapeutic targeting of PP2A in cancer can be completed through either enzyme inhibitors or activators. PP2A modulators likewise tend to be effective in drug-resistant cancers and work synergistically with other known cancer therapeutics. In this review, we will discuss the patterns of PP2A deregulation in cancer, and its known downstream signaling pathways important for cancer regulation, along with many activators and inhibitors of PP2A known to inhibit cancer progression.

Impact of DNA ligase inhibition on the nick sealing of polß nucleotide insertion products at the downstream steps of base excision repair pathway.

DNA ligase (LIG) I and IIIα finalize base excision repair (BER) by sealing a nick product after nucleotide insertion by DNA polymerase (pol) ß at the downstream steps. We previously demonstrated that a functional interplay between polß and BER ligases is critical for efficient repair, and polß mismatch or oxidized nucleotide insertions confound final ligation step. Yet, how targeting downstream enzymes with small molecule inhibitors could affect this coordination remains unknown. Here, we report that DNA ligase inhibitors, L67 and L82-G17, slightly enhance hypersensitivity to oxidative stress-inducing agent, KBrO3, in polß+/+ cells more than polß-/- null cells. We showed less efficient ligation after polß nucleotide insertions in the presence of the DNA ligase inhibitors. Furthermore, the mutations at the ligase inhibitor binding sites (G448, R451, A455) of LIG1 significantly affect nick DNA binding affinity and nick sealing efficiency. Finally, our results demonstrated that the BER ligases seal a gap repair intermediate by the effect of polß inhibitor that diminishes gap filling activity. Overall, our results contribute to understand how the BER inhibitors against downstream enzymes, polß, LIG1, and LIGIIIα, could impact the efficiency of gap filling and subsequent nick sealing at the final steps leading to the formation of deleterious repair intermediates.

An evolutionary non-conserved motif in Helicobacter pylori arginase mediates positioning of the loop containing the catalytic residue for catalysis.

The binuclear metalloenzyme Helicobacter pylori arginase is important for pathogenesis of the bacterium in the human stomach. Despite conservation of the catalytic residues, this single Trp enzyme has an insertion sequence (-153ESEEKAWQKLCSL165-) that is extremely crucial to function. This sequence contains the critical residues, which are conserved in the homolog of other Helicobacter gastric pathogens. However, the underlying basis for the role of this motif in catalytic function is not completely understood. Here, we used biochemical, biophysical and molecular dynamics simulations studies to determine that Glu155 of this stretch interacts with both Lys57 and Ser152. These interactions are essential for positioning of the motif through Trp159, which is located near Glu155 (His122-Trp159-Tyr125 contact is essential to tertiary structural integrity). The individual or double mutation of Lys57 and Ser152 to Ala considerably reduces catalytic activity with Lys57 to Ala being more significant, indicating they are crucial to function. Our data suggest that the Lys57-Glu155-Ser152 interaction influences the positioning of the loop containing the catalytic His133 so that this His can participate in catalysis, thereby providing a mechanistic understanding into the role of this motif in catalytic function. Lys57 was also found only in the arginases of other Helicobacter gastric pathogens. Based on the non-conserved motif, we found a new molecule, which specifically inhibits this enzyme. Thus, the present study not only provides a molecular basis into the role of this motif in function, but also offers an opportunity for the design of inhibitors with greater efficacy.

Therapeutics Targeting p53-MDM2 Interaction to Induce Cancer Cell Death.

Named as the guardian of the genome, p53 is a tumor suppressor that regulates cell function, often through many different mechanisms such as DNA repair, apoptosis, cell cycle arrest, senescence, metabolism, and autophagy. One of the genes that p53 activates is MDM2, which forms a negative feedback loop since MDM2 induces the degradation of p53. When p53 activity is inhibited, damaged cells do not undergo cell cycle arrest or apoptosis. As 50% of human cancers inactivate p53 by mutation, current research focuses on reactivating p53 by developing drugs that target the p53-MDM2 interaction, which includes the binding of MDM2 and phosphorylation of p53. The objective of this article is to provide a short list and description of p53-MDM2 antagonists that may be excellent candidates for inducing cancer cell death. Relevant articles were searched for and identified using online databases such as PubMed and ScienceDirect. Increasing p53 levels, by targeting the p53-MDM2 interaction, can help p53 play its role as a tumor suppressor and induce cancer cell death. Researchers have identified different compounds that can act as inhibitors, either by directly binding to MDM2 or by modifying p53 with phosphorylation. The results associated with the drugs demonstrate the importance of targeting such interactions to inhibit cancer cell growth, which indicates that the use of the compounds may improve cancer therapeutics.

Insight into the Excitation-Dependent Fluorescence of Carbon Dots.

High quantum yield, photoluminescence tunability, and sensitivity to the environment are a few distinct trademarks that make carbon nanodots (CDs) interesting for fundamental research, with potential to replace the prevalent inorganic semiconductor quantum dots. Currently, application and fundamental understanding of CDs are constrained because it is difficult to make a quantitative comparison among different types of CDs simply because their photoluminescence properties are directly linked to their size distribution, the surface functionalization, the carbon core structures (graphitic or amorphous) and the number of defects. Herein, we report a facile one-step synthesis of mono-dispersed and highly fluorescent nanometre size CDs from a 'family' of glucose-based sugars. These CDs are stable in aqueous solutions with photoluminescence in the visible range. Our results show several common features in the family of CDs synthesized in that the fluorescence, in the visible region, is due to a weak absorption in the 300-400 nm from a heterogeneous population of fluorophores. Fluorescence quenching experiments suggest the existence of not only surface-exposed fluorophores but more importantly solvent inaccessible fluorophores present within the core of CDs. Interestingly, time-resolved fluorescence anisotropy experiments directly suggest that a fast exchange of excitation energy occurs that results in a homo-FRET based depolarization within 150 ps of excitation.

Site-specific fluorescence dynamics in an RNA 'thermometer' reveals the role of ribosome binding in its temperature-sensitive switch function.

RNA thermometers control the translation of several heat shock and virulence genes by their temperature-sensitive structural transitions. Changes in the structure and dynamics of MiniROSE RNA, which regulates translation in the temperature range of 20-45°C, were studied by site specifically replacing seven adenine residues with the fluorescent analog, 2-aminopurine (2-AP), one at a time. Dynamic fluorescence observables of 2-AP-labeled RNAs were compared in their free versus ribosome-bound states for the first time. Noticeably, position dependence of fluorescence observables, which was prominent at 20°C, was persistent even at 45ºC, suggesting the persistence of structural integrity up to 45ºC. Interestingly, position-dependent dispersion of fluorescence lifetime and quenching constant at 45°C was ablated in ribosome-bound state, when compared to those at 20°C, underscoring loss of structural integrity at 45°C, in ribosome-bound RNA. Significant increase in the value of mean lifetime for 2-AP corresponding to Shine-Dalgarno sequences, when the temperature was raised from 20 to 45°C, to values seen in the presence of urea at 45°C was a strong indicator of melting of the 3D structure of MiniROSE RNA at 45°C, only when it was ribosome bound. Taken all together, we propose a model where we invoke that ribosome binding of the RNA thermometer critically regulates temperature sensing functions in MiniROSE RNA.

Mode of DNA binding with γ-butyrolactone receptor protein CprB from Streptomyces coelicolor revealed by site-specific fluorescence dynamics.

BACKGROUND: The γ-butyrolactone (GBL) binding transcription factors in Streptomyces species are known for their involvement in quorum sensing where they control the expression of various genes initiating secondary metabolic pathways. The structurally characterized member of this family CprB from Streptomyces coelicolor had earlier been demonstrated to bind a multitude of sequences containing a specific binding signature. Though structural breakthrough has been obtained for its complex with a consensus DNA sequence there is, however a dearth of information regarding the overall and site specific dynamics of protein-DNA interaction. METHODS: To delineate the effect of CprB on the bound DNA, changes in motional dynamics of the fluorescent probe 2-aminopurine were monitored at three conserved base positions (5th, 12th and 23rd) for two DNA sequences: the consensus and the biologically relevant cognate element, on complex formation. RESULTS: The changes in lifetime and generalized order parameter revealed a similarity in the binding pattern of the protein to both sequences with greater dynamic restriction at the end positions, 5th and 23rd, as compared to the middle 12th position. Also differences within this pattern demonstrated the influence of even small changes in sequence on protein interactions. CONCLUSIONS: Here the study of motional dynamics was instrumental in establishing a structural footprint for the cognate DNA sequence and explaining the dynamics for the consensus DNA from structural correspondence. GENERAL SIGNIFICANCE: Motional dynamics can be a powerful tool to efficiently study the mode of DNA binding to proteins that interact differentially with a plethora of DNA sequences, even in the absence of structural breakthrough.

Cyclin-Dependent Kinase Inhibitors as Anticancer Therapeutics.

Cyclin-dependent kinases (CDKs) have been considered promising drug targets for a number of years, but most CDK inhibitors have failed rigorous clinical testing. Recent studies demonstrating clear anticancer efficacy and reduced toxicity of CDK4/6 inhibitors such as palbociclib and multi-CDK inhibitors such as dinaciclib have rejuvenated the field. Favorable results with palbociclib and its recent U.S. Food and Drug Administration approval demonstrate that CDK inhibitors with narrow selectivity profiles can have clinical utility for therapy based on individual tumor genetics. A brief overview of results obtained with ATP-competitive inhibitors such as palbociclib and dinaciclib is presented, followed by a compilation of new avenues that have been pursued toward the development of novel, non-ATP-competitive CDK inhibitors. These creative ways to develop CDK inhibitors are presented along with crystal structures of these agents complexed with CDK2 to highlight differences in their binding sites and mechanisms of action. The recent successes of CDK inhibitors in the clinic, combined with the potential for structure-based routes to the development of non-ATP-competitive CDK inhibitors, and evidence that CDK inhibitors may have use in suppressing chromosomal instability and in synthetic lethal drug combinations inspire optimism that CDK inhibitors will become important weapons in the fight against cancer.

Comparison of single versus multiple fractions for palliative treatment of painful bone metastasis: first study from north west India.

BACKGROUND: Bone metastasis is a usual cause of pain in advanced cancer. Conventional radiation schedules require larger hospital stay and thus are not suitable for patients with poor general condition. This prospective observational study aims to compare the pain-relieving efficacy of different radiation fractionation schedules, i.e., 8 Gy administered in a single fraction versus 30 Gy administered in 10 fractions. MATERIALS AND METHODS: Two hundred and fifty consecutive patients of bone metastasis were evaluated for the study, with 63 patients being excluded due to non-fulfillment of the inclusion criteria. The response to radiotherapy leading to pain relief as per the Visual Analog Scale was recorded at the end of treatment, 8 days, 15 days and 1 month during the follow-up visits. RESULTS: Sixty-two percent of the patients received a single fraction while the remaining received 10 fractions. In the 10-fraction group, overall response was present in 60% of the patients. Stable pain was present in 23% of the patients while 9% patients had progressive pain. At 1 month of completion of treatment, 9% patients were lost to follow-up. In the single-fraction arm, overall response was seen in 58%, stable pain in 27% and progressive pain in 7% of the patients. Six percent of the patients were lost to follow-up. CONCLUSIONS: Single-fraction treatment for bony metastasis is as effective as multiple fractions to relieve bony pain and provides treatment convenience to both the patient and the caregiver.

Analysis of patterns of palliative radiotherapy in north west India: a regional cancer center experience.

BACKGROUND: Palliative radiotherapy (PRT) is the eventual requirement in 30-50% of all cancer patients. PRT is primarily aimed to relieve pain and prevent/treat collapse or fracture in case of bone metastasis, to reduce edema in patients with cranial metastasis, and to control distressing symptoms of rapid primary growth. An audit of PRT planned in a busy cancer center can help in the characterization of the requirements of the patients and the formulation of institutional policies. MATERIALS AND METHODS: In total, 516 patients who received PRT in our regional cancer center from January 2012 to December 2012 and whose complete records were available for analysis were selected for this retrospective study. Medical records and radiotherapy files were analyzed to obtain data such as sociodemographic parameters, prescription of PRT, and follow up. Descriptive statistics were evaluated in terms of frequencies and percentages to allow comparisons. RESULTS: Of the 516 patients, 73% patients were male; the median age of the patients receiving PRT was 62 years (range 13-83 years). About 48% (n = 248) patients received PRT at the primary site while rest (52%) were given PRT at the metastatic site. The most common indication of PRT was pain (56.8% cases), followed by cytostatic PRT (19.8%) and raised ICT (12.4%). The median dose prescribed was 30 Gy (range 8-36 Gy) delivered in 1-12 fractions over the duration of 1-18 days. The overall response rate was about 43% at 2 weeks of completion of PRT; the median follow-up of the patients was 154 days (range 9-256 days). The long-term symptom relief at median follow up was 8%. CONCLUSIONS: Good clinical judgment and expertise is required in prescribing correct fractionation schedule to achieve effective symptom palliation with lowest possible cost and inconvenience to the patients and relatives. Hypofractionated radiotherapy is a feasible treatment option in patients with advanced incurable disease to achieve effective palliation.

Anti-tumor activity of novel biisoquinoline derivatives against breast cancers.

Breast cancer is classified into three groups according to its expression of hormone/growth factor receptors: (i) estrogen receptor (ER) and progesterone receptor (PR)-positive; (ii) human epidermal growth factor receptor 2 (HER2)-positive; and (iii) ER, PR, and HER2-negative (triple-negative). A series of methoxy-substituted biisoquinoline compounds have been synthesized as a potential chemotherapeutic agent for the triple-negative breast cancers which are especially challenging to manage. Structure activity relationship study revealed that rigid 6,6'-dimethoxy biisoquinoline imidazolium compound (1c, DH20931) exhibited the significant growth inhibitory effects on both triple-positive and triple-negative human breast cancer cell lines with IC50 in the range of 0.3-3.9 µM. The 1c (DH20931) is more potent than structurally related noscapine for growth inhibition of MCF7 cell line (IC50=1.3 vs 57 µM) and MDA-MB231 cell line (IC50=3.9 vs 64 µM).

Molecular editing of NSC-666719 enabling discovery of benzodithiazinedioxide-guanidines as anticancer agents.

DNA polymerase ß (Polß) is crucial for the base excision repair (BER) pathway of DNA damage repair and is an attractive target for suppressing tumorigenesis as well as chemotherapeutic intervention of cancer. In this study, a unique strategy of scaffold-hopping-based molecular editing of a bioactive agent NSC-666719 was investigated, which led to the development of new molecular motifs with Polß inhibitory activity. NSC compound and its analogs (two series) were prepared, focusing on pharmacophore-based molecular diversity. Most compounds showed higher activities than the parent NSC-666719 and exhibited effects on apoptosis. The inhibitory activity of Polß was evaluated in both in vitro reconstituted and in vivo intact cell systems. Compound 10e demonstrated significant Polß interaction and inhibition characteristics, including direct, non-covalent, reversible, and comparable binding affinity. The investigated approach is useful, and the discovered novel analogs have a high potential for developing as anticancer therapeutics.

Multiple unfolding pathways of leucine binding protein (LBP) probed by single-molecule force spectroscopy (SMFS).

Experimental studies on the folding and unfolding of large multi-domain proteins are challenging, given the proteins' complex energy landscapes with multiple intermediates. Here, we report a mechanical unfolding study of a 346-residue, two-domain leucine binding protein (LBP) from the bacterial periplasm. Forced unfolding of LBP is a prerequisite for its translocation across the cytoplasmic membrane into the bacterial periplasm. During the mechanical stretching of LBP, we observe that 38% of the unfolding flux followed a two-state pathway, giving rise to a single unfolding force peak at ~70 pN with an unfolding contour length of 120 nm in constant-velocity single-molecule pulling experiments. The remaining 62% of the unfolding flux followed multiple three-state pathways, with intermediates having unfolding contour lengths in the range ~20-85 nm. These results suggest that the energy landscape of LBP is complex, with multiple intermediate states, and a large fraction of molecules go through intermediate states during the unfolding process. Furthermore, the presence of the ligand leucine increased the unfolding flux through the two-state pathway from 38% to 65%, indicating the influence of ligand binding on the energy landscape. This study suggests that unfolding through parallel pathways might be a general mechanism for the large two-domain proteins that are translocated to the bacterial periplasmic space.

All EGFR mutations are (not) created equal: focus on uncommon EGFR mutations.

PURPOSE: Most common EGFR mutations in NSCLC include del19 and exon 21 L858R. Approximately 10% of patients have uncommon EGFR mutations (indels, missense mutations involving G719, L861 and S768 codons, and exon 20 insertions) that do not respond to TKIs. METHODS: Of 490 EGFR mutated NSCLC samples, 60 cases harboring uncommon/compound EGFR mutations were reviewed retrospectively, and 44 were included for survival analysis. RESULTS: Sixty (12.2%) patients with a median age of 63 years (25-84 years) had uncommon/compound EGFR mutations. Majority had no history of smoking (52; 86.7%). Most common major uncommon mutations (G719X in exon 18, L861Q in exon 21 and S768I in exon 20) were identified in 19 (31.7%) patients. 17 (28.3%) cases demonstrated exon 20 insertions. De novo T790M was observed in 7 (11.7%) cases and 9 cases exhibited compound/dual mutations. Among the 12 patients who received first-line EGFR TKI, 7 received afatinib. Median progression-free survival of patients following first-line afatinib was 8.13 months, irrespective of mutation type exhibited. Overall response rate to first-line afatinib therapy was 57.1%. CONCLUSION: The current study highlighted that rare/dual EGFR mutations are heterogeneous with distinct clinical features in a large Indian cohort of EGFR mutated patients with NSCLC.

EEPD1 promotes repair of oxidatively-stressed replication forks.

Unrepaired oxidatively-stressed replication forks can lead to chromosomal instability and neoplastic transformation or cell death. To meet these challenges cells have evolved a robust mechanism to repair oxidative genomic DNA damage through the base excision repair (BER) pathway, but less is known about repair of oxidative damage at replication forks. We found that depletion or genetic deletion of EEPD1 decreases clonogenic cell survival after oxidative DNA damage. We demonstrate that EEPD1 is recruited to replication forks stressed by oxidative damage induced by H2O2 and that EEPD1 promotes replication fork repair and restart and decreases chromosomal abnormalities after such damage. EEPD1 binds to abasic DNA structures and promotes resolution of genomic abasic sites after oxidative stress. We further observed that restoration of expression of EEPD1 via expression vector transfection restores cell survival and suppresses chromosomal abnormalities induced by oxidative stress in EEPD1-depleted cells. Consistent with this, we found that EEPD1 preserves replication fork integrity by preventing oxidatively-stressed unrepaired fork fusion, thereby decreasing chromosome instability and mitotic abnormalities. Our results indicate a novel role for EEPD1 in replication fork preservation and maintenance of chromosomal stability during oxidative stress.

Solvent-induced tuning of internal structure in a protein amyloid protofibril.

An important goal in studies of protein aggregation is to obtain an understanding of the structural diversity that is characteristic of amyloid fibril and protofibril structures at the molecular level. In this study, what to our knowledge are novel assays based on time-resolved fluorescence anisotropy decay and dynamic quenching measurements of a fluorophore placed at different specific locations in the primary structure of a small protein, barstar, have been used to determine the extent to which the protein sequence participates in the structural core of protofibrils. The fluorescence measurements reveal the structural basis of how modulating solvent polarity results in the tuning of the protofibril conformation from a pair of parallel ß-sheets in heat-induced protofibrils to a single parallel ß-sheet in trifluorethanol-induced protofibrils. In trifluorethanol-induced protofibrils, the single ß-sheet is shown to be built up from in-register ß-strands formed by nearly the entire protein sequence, while in heat-induced protofibrils, the pair of ß-sheets motif is built up from ß-strands formed by only the last two-third of the protein sequence.

Hepatocellular Carcinoma (HCC) in North-Western India: A Retrospective Study Focusing on Epidemiology, Risk Factors, and Survival.

BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive tumour with unpredictable outcome. It is fourth most common cause of cancers in India. However, information on HCC is inadequate in India. Therefore, the purpose of study is to determine overall survival for patients diagnosed with HCC and association between various predictive factors and survival. METHODS: Retrospectively 59 patients of HCC presenting to the radiotherapy out-patient department of our institute from April 2015 to April 2018 were included in the study. RESULTS: The median overall survival (OS) was 5 months ranging from 0 to 13 months. Majority of patients were in advance stage (III/IV). All patient died by 13 months. None of the possible predictive factors were found to be significantly associated with survival (p > 0.05) by univariate analysis. However, age < 59 years, male gender, KPS ≤ 60, AFP ≥ 400, cirrhosis, multifocality, tumour size > 10 cm, advance stage (IIIB/IV), Child-Pugh score B/C, CLIP score ≥ 4, and raised bilirubin level had poorer survival compared to other predictive factors. Median survival was better in patient treated with TACE followed by sorafenib + palliative care group (9 months) then sorafenib + palliative care and palliative care alone group (5 and 4 months respectively). Although results were not statistically significant (p = 0.133). Amongst all possible variables, highest hazard was found with multifocal lesion (2.058) and results were statistically significantly (p = 0.045, 95% confidence interval: 0.922 to 4.590) as compared to unifocal lesion with median survival period of 7 vs 9.5 months by Kaplan-Meier survival curve analysis using log rank test. CONCLUSION: Multifocality was independent predicator for poor survival in HCC. Further clinical studies are necessary to improve the outcomes of patients with high risk features.

Co-relation of SARS-CoV-2 related 30-d mortality with HRCT score and RT-PCR Ct value-based viral load in patients with solid malignancy.

BACKGROUND: Coronavirus disease 2019 (COVID-19) patients with malignancy are published worldwide but are lacking in data from India. AIM: To characterize COVID-19 related mortality outcomes within 30 d of diagnosis with HRCT score and RT-PCR Ct value-based viral load in various solid malignancies. METHODS: Patients included in this study were with an active or previous malignancy and with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the institute database. We collected data on demographic details, baseline clinical conditions, medications, cancer diagnosis, treatment and the COVID-19 disease course. The primary endpoint was the association between the mortality outcome and the potential prognostic variables, specially, HRCT score, RT-PCR Ct value-based viral load, etc. using logistic regression analyses treatment received in 30 d. RESULTS: Out of 131 patients, 123 met inclusion criteria for our analysis. The median age was 57 years (interquartile range = 19-82) while 7 (5.7%) were aged 75 years or older. The most prevalent malignancies were of GUT origin 49 (39.8%), hepatopancreatobiliary (HPB) 40 (32.5%). 109 (88.6%) patients were on active anticancer treatment, 115 (93.5%) had active (measurable) cancer. At analysis on May 20, 2021, 26 (21.1%) patients had died. In logistic regression analysis, independent factors associated with an increased 30-d mortality were in patients with the symptomatic presentation. Chemotherapy in the last 4 wk, number of comorbidities (≥ 2 vs none: 3.43, 1.08-8.56). The univariate analysis showed that the risk of death was significantly associated with the HRCT score: for moderate (8-15) [odds ratio (OR): 3.44; 95% confidence interval (CI): 1.3-9.12; P = 0.0132], severe (> 15) (OR: 7.44; 95%CI: 1.58-35.1; P = 0.0112). CONCLUSION: To the best of our knowledge, this is the first study from India reporting the association of HRCT score and RT-PCR Ct value-based 30-d mortality outcomes in SARS-CoV-2 infected cancer patients.

Serpentine Supra-venous Hyperpigmentation "Badge of Courage" in Fight Against Cancer: An Brief Review.

Persistent serpentine supra-venous hyperpigmentation (PSSH) describes a hyperpigmentation of the skin overlying peripheral veins with characteristic of underlying vessels that are patent. It has been described most commonly after injection of chemotherapeutic drugs. We describe a 44 year old man with diagnosed case of Ca stomach on FOLFOX based chemotherapy. After the 1st cycle of Chemotherapy he developed serpentine supra-venous hyperpigmentation. Introduction: Conventional chemotherapy agents commonly cause infusion-site lesions, such as chemical cellulitis due to drug extravasation and evanescent eruptions.(1) 5-Fluorouracil (5-FU) is a cytotoxic agent used mostly in combination to treat a variety of malignant disorders. Hyperpigmentation is a rare side effect occurring with 5-FU infusions; it has been reported in 2-5% of patients. Various types of pigmentary abnormalities have been reported with 5-FU use such as diffuse hyperpigmentation of the face and palms, macular pigmentary changes on the palms and soles, hyperpigmentation overlying the superficial venous network also called serpentine supravenous hyperpigmentation (SSH) and persistent supravenous erythematous eruptions (PSEE).(2) Keywords: Serpentine Supra-venous Hyperpigmentation, Dermatological toxicity, Fluorouracil.

Sensitization of FOLFOX-resistant colorectal cancer cells via the modulation of a novel pathway involving protein phosphatase 2A.

The treatment of colorectal cancer (CRC) with FOLFOX shows some efficacy, but these tumors quickly develop resistance to this treatment. We have observed increased phosphorylation of AKT1/mTOR/4EBP1 and levels of p21 in FOLFOX-resistant CRC cells. We have identified a small molecule, NSC49L, that stimulates protein phosphatase 2A (PP2A) activity, downregulates the AKT1/mTOR/4EBP1-axis, and inhibits p21 translation. We have provided evidence that NSC49L- and TRAIL-mediated sensitization is synergistically induced in p21-knockdown CRC cells, which is reversed in p21-overexpressing cells. p21 binds with procaspase 3 and prevents the activation of caspase 3. We have shown that TRAIL induces apoptosis through the activation of caspase 3 by NSC49L-mediated downregulation of p21 translation, and thereby cleavage of procaspase 3 into caspase 3. NSC49L does not affect global protein synthesis. These studies provide a mechanistic understanding of NSC49L as a PP2A agonist, and how its combination with TRAIL sensitizes FOLFOX-resistant CRC cells.