New Genetic Markers of Skin T-Cell Lymphoma Treatment.

AIM: Cutaneous T-cell lymphomas (CTCL) can be described as chronic skin inflammation lesions with the content of malignant T cells and they are considered to be T-cell-mediated skin diseases. CD147 is recognized as a 58-kDa cell surface glycoprotein of the immunoglobulin superfamily; it can induce the synthesis of MMPs (matrix metalloproteinases) on the surface of tumor cells where it was originally identified. It can also function in adjacent tumor fibroblasts using CD147-CD147 interactions. The polymorphism rs8259 T/A is situated in the untranslated region (3'UTR) of the CD147 gene. HLA DRB1*1501 takes part in the process of presentation and recognition of different antigens to T cells. It can be expressed by antigen-presenting cells-macrophages, dendritic cells, and B cells. The aim of the study is to test genotype-phenotype associations of both polymorphisms including therapy in a large cohort of CTCL patients. MATERIALS AND METHODS: A final total of 104 CTCL patients were enrolled in the study. For the first remission at the clinic department, they were treated by means of local skin-directed therapy, phototherapy, and systemic therapy. Genomic DNA was isolated from peripheral blood leukocytes. A standard technique using proteinase K was applied. The polymorphisms rs8259 T/A (CD147 gene) and rs3135388 (HLA DRB1*1501) were detected through standard PCR-restriction fragment length polymorphism methods. RESULTS: The severity of the disease (patients with parapsoriasis, stages IA and IB, vs patients with stages IIB, IIIA, and IIIB) was associated with the CD147 genotype: the AA variant was 3.38 times more frequent in more severe cases, which reflects the decision on systemic therapy (p = 0.02, specificity 0.965). The AA genotype in the CD147 polymorphism was 12 times more frequent in patients who underwent systemic therapy of CTCL compared to those not treated with this therapy (p = 0.009, specificity 0.976). The same genotype was also associated with radiotherapy-it was observed 14 times more frequently in patients treated with radiotherapy (p = 0.009, specificity 0.959). In patients treated with interferon α therapy, the AA genotype was observed to be 5.85 times more frequent compared to the patients not treated with interferon therapy (p = 0.03, specificity 0.963). The HLA DRB1*1501 polymorphism was associated with local skin-directed therapy of CTCL. The CC genotype of the polymorphism was observed to be 3.57 times more frequent in patients treated with local therapy (p = 0.008, specificity 0.948). When both polymorphisms had been calculated together, even better results were obtained: the AACC double genotype was 11 times more frequent in patients with severe CTCL (p = 0.009, specificity 0.977). The TACT double genotype was associated with local skin-directed therapy (0.09 times lower frequency, p = 0.007, sensitivity 0.982). The AACC genotype was 8.9 times more frequent in patients treated by means of systemic therapy (p = 0.02, specificity 0.976) and as many as 18.8 times more frequent in patients treated with radiotherapy (p = 0.005, specificity 0.969). Thus, the AACC double genotype of CD147 and DRB1*1501 polymorphisms seems to be a clinically highly specific marker of severity, systemic therapy and radiotherapy of patients with T-cell lymphoma. CONCLUSION: Although genotyping results were not known during the treatment decision and could not modify it, the clinical decision on severity and therapy reflected some aspects of the genetic background of this complicated T-cell-associated disease very well.

Angioimmunoblastic T-cell Lymphoma Mimicking Systemic Lupus Erythematosus: A Case Report and Literature Review.

Objective: This study aimed to investigate the clinical features of angioimmunoblastic T-cell lymphoma (AITL) mimicking systemic lupus erythematosus (SLE) and raise awareness about AITL among rheumatologists in order to prevent misdiagnosis and missed diagnosis. The study reports on a case of AITL mimicking SLE and provides a literature review. Methods: Using key words as search terms, relevant articles published in PubMed before 2022-05 were searched, and their clinical characteristics were collected and analyzed. Results: The literature review retrieved six case reports, including four cases initially diagnosed with SLE and then with AITL. The other two case diagnoses were SLE and AITL, respectively. The two diseases are pathogenically associated and share some common features. The clinical manifestations of AITL are complex. The disease is closely associated with abnormal immune functions and is highly heterogeneous. Conclusion: Patients with AITL generally have a poor prognosis. Rarely do reported cases show AITL mimicking SLE. AITL should be considered during clinical practice to prevent missed diagnoses or misdiagnoses.

Primary Breast Natural Killer/T-cell lymphoma with Cutaneous Involvement: A Case Report.

Objective: Extranodal natural killer/T-cell lymphoma comprises less than 1% of all non-Hodgkin lymphomas. It is rare in Western countries but is common in East Asia and Central and South America. The pathological features are angiocentricity /angioinvasion and significant tissue necrosis. Case Presentation: A 72-year-old woman was diagnosed with primary breast extranodal natural killer/T-cell lymphoma. The patient presented with a painless right breast tumor and had uneven internal echo and strip blood flow signal on breast ultrasonography. After right breast tumor resection, the pathological diagnosis was extranodal natural killer/T-cell lymphoma. Despite receiving CHOP chemotherapy, the patient died of lymphoma and multiple organ dysfunction syndrome 27 months after diagnosis. Conclusion: Extranodal natural killer/T-cell lymphoma with breast tissue as the primary site is very rare. The disease is prone to misdiagnosis and missed diagnosis, and diagnosis by ultrasound is difficult, so pathological examination after biopsy is particularly important.

Guideline Concordance of Treatment and Outcomes Among Adult Non-Hodgkin Lymphoma Patients in Sub-Saharan Africa: A Multinational, Population-Based Cohort.

BACKGROUND: Although non-Hodgkin lymphoma (NHL) is the 6th most common malignancy in Sub-Saharan Africa (SSA), little is known about its management and outcome. Herein, we examined treatment patterns and survival among NHL patients. METHODS: We obtained a random sample of adult patients diagnosed between 2011 and 2015 from 11 population-based cancer registries in 10 SSA countries. Descriptive statistics for lymphoma-directed therapy (LDT) and degree of concordance with National Comprehensive Cancer Network (NCCN) guidelines were calculated, and survival rates were estimated. FINDINGS: Of 516 patients included in the study, sub-classification was available for 42.1% (121 high-grade and 64 low-grade B-cell lymphoma, 15 T-cell lymphoma and 17 otherwise sub-classified NHL), whilst the remaining 57.9% were unclassified. Any LDT was identified for 195 of all patients (37.8%). NCCN guideline-recommended treatment was initiated in 21 patients. This corresponds to 4.1% of all 516 patients, and to 11.7% of 180 patients with sub-classified B-cell lymphoma and NCCN guidelines available. Deviations from guideline-recommended treatment were initiated in another 49 (9.5% of 516, 27.2% of 180). By registry, the proportion of all patients receiving guideline-concordant LDT ranged from 30.8% in Namibia to 0% in Maputo and Bamako. Concordance with treatment recommendations was not assessable in 75.1% of patients (records not traced (43.2%), traced but no sub-classification identified (27.8%), traced but no guidelines available (4.1%)). By registry, diagnostic work-up was in part importantly limited, thus impeding guideline evaluation significantly. Overall 1-year survival was 61.2% (95%CI 55.3%-67.1%). Poor ECOG performance status, advanced stage, less than 5 cycles and absence of chemo (immuno-) therapy were associated with unfavorable survival, while HIV status, age, and gender did not impact survival. In diffuse large B-cell lymphoma, initiation of guideline-concordant treatment was associated with favorable survival. INTERPRETATION: This study shows that a majority of NHL patients in SSA are untreated or undertreated, resulting in unfavorable survival. Investments in enhanced diagnostic services, provision of chemo(immuno-)therapy and supportive care will likely improve outcomes in the region.

Epstein-Barr virus-positive mucocutaneous ulcer, plasmablastic type, associated with nodal CD4+ angioimmunoblastic T-cell lymphoma and generalised pruritus: a self-limiting lymphoproliferative disorder resembling cutaneous plasmablastic lymphoma.

A woman in her 80s reported of generalised pruritus, which was treated with phototherapy and steroid administration. Two months after onset, lymph node biopsy revealed CD4+ angioimmunoblastic T-cell lymphoma with systemic superficial nodal involvement. Intractable prurigo was judged as T-cell lymphoma related. After effective chemotherapy (7 months later), skin nodules appeared multifocally, including on the lip, thumb and lower leg. The biopsied infiltrative lesion on the right lower leg microscopically revealed subcutaneous growth of atypical plasmablasts with nearly 100% Ki-67 labelling and Epstein-Barr virus (EBV)-encoded small nuclear RNA positivity. Plasmablastic lymphoma (CD45/CD19/CD38/CD138/MUM1+, CD20/CD79a/PAX5-) was suspected. Immunoglobulin light-chain restriction and nuclear expression of c-myc protein were undetectable, and the ulcers were spontaneously epithelialised by the cessation of steroid administration. After 10 months, non-progressive prurigos persisted on the extremities, but without regrowth of nodal T-cell lymphoma and cutaneous lymphoproliferative lesion. Reactive nature of the EBV-induced mucocutaneous plasmablastic growth (EBV-positive mucocutaneous ulcer, plasmablastic type) is discussed.

T-cell-lymphoma presented as a solitary subcutaneous mass in the ventral cervical region of an adult llama- diagnostic and treatment.

BACKGROUND: Neoplasm in South American camelids (SAC) are commonly described. The most frequently reported type of neoplasm are lymphomas and difference in the age suffering from lymphomas of and llamas is seen. This report describes a case of a solitary lymphoma in a 5 years and 9 month old llama mare displaying the approach of diagnostic imaging and successful surgical treatment. CASE PRESENTATION: The llama was referred to the clinic for dyspnoea and inspiratory abnormal respiratory sounds. The clinical examination comprised blood cell count, ultrasonographic and radiographic examinations, endoscopy and fine needle aspiration cytology of a mass detected in the mid cervical region. The mass was surgically removed. Histopathological examination of the surgically removed mass diagnosed a malignant T-cell- lymphoma. According to the results of the clinical, ultrasonographic and radiographic examinations no tumor invasion was apparent in distant organs and the llama was discharged from the clinic seven days after surgery. CONCLUSION: Lymphoma has been reported to be the most common neoplasia in camelids and are more often described in young alpacas and in adult llamas. To the author´s knowledge the case presented here is the first that described a broad panel of diagnostic tools including ultrasound, radiographs, endoscopy, fine needle aspiration cytology and histopathoogical examination as well as a successful surgical treatment of a solitary lymphoma in camelids.

One-Two Punch Therapy for the Treatment of T-Cell Malignancies Involving p53-Dependent Cellular Senescence.

T-cell malignancies are still difficult to treat due to a paucity of plans that target critical dependencies. Drug-induced cellular senescence provides a permanent cell cycle arrest during tumorigenesis and cancer development, particularly when combined with senolytics to promote apoptosis of senescent cells, which is an innovation for cancer therapy. Here, our research found that wogonin, a well-known natural flavonoid compound, not only had a potential to inhibit cell growth and proliferation but also induced cellular senescence in T-cell malignancies with nonlethal concentration. Transcription activity of senescence-suppression human telomerase reverse transcriptase (hTERT) and oncogenic C-MYC was suppressed in wogonin-induced senescent cells, resulting in the inhibition of telomerase activity. We also substantiated the occurrence of DNA damage during the wogonin-induced aging process. Results showed that wogonin increased the activity of senescence-associated ß-galactosidase (SA-ß-Gal) and activated the DNA damage response pathway mediated by p53. In addition, we found the upregulated expression of BCL-2 in senescent T-cell malignancies because of the antiapoptotic properties of senescent cells. Following up this result, we identified a BCL-2 inhibitor Navitoclax (ABT-263), which was highly effective in decreasing cell viability and inducing apoptotic cell death in wogonin-induced senescent cells. Thus, the "one-two punch" approach increased the sensibility of T-cell malignancies with low expression of BCL-2 to Navitoclax. In conclusion, our research revealed that wogonin possesses potential antitumor effects based on senescence induction, offering a better insight into the development of novel therapeutic methods for T-cell malignancies.

Sesamin promotes apoptosis and pyroptosis via autophagy to enhance antitumour effects on murine T-cell lymphoma.

Sesamin is a lignan compound in plants that has various pharmacological effects, including reducing diabetes-associated injuries, regulating fatty acid and cholesterol metabolism, and exerting antiinflammatory and antitumour effects. Previous studies have reported that sesamin can inhibit the proliferation of several types of tumour cells and exert antitumour effects. However, the antitumour effect of sesamin on T-cell lymphoma is still unknown. In this study, we selected a T-cell lymphoma mouse model to investigate the mechanism of sesamin against T-cell lymphoma via programmed cell death in vivo and in vitro. We found that sesamin could significantly inhibit the growth of EL4 cells in a tumour-bearing mouse model. Sesamin markedly inhibited the proliferation of EL4 cells by inducing apoptosis, pyroptosis and autophagy. Autophagy occurred earlier than apoptosis and pyroptosis in EL4 cells after sesamin treatment. Blocking autophagy inhibited apoptosis and pyroptosis in EL4 cells after sesamin treatment. Taken together, these results suggested that sesamin promoted apoptosis and pyroptosis via autophagy to enhance antitumour effects on murine T-cell lymphoma. This study expands our knowledge of the pharmacological effects of sesamin on T-cell lymphoma, and provides a theoretical basis for the development of new antitumour drugs and treatments for T-cell lymphoma.

Therapeutic targeting of the mitochondrial one-carbon pathway: perspectives, pitfalls, and potential.

Most of the drugs currently prescribed for cancer treatment are riddled with substantial side effects. In order to develop more effective and specific strategies to treat cancer, it is of importance to understand the biology of drug targets, particularly the newly emerging ones. A comprehensive evaluation of these targets will benefit drug development with increased likelihood for success in clinical trials. The folate-mediated one-carbon (1C) metabolism pathway has drawn renewed attention as it is often hyperactivated in cancer and inhibition of this pathway displays promise in developing anticancer treatment with fewer side effects. Here, we systematically review individual enzymes in the 1C pathway and their compartmentalization to mitochondria and cytosol. Based on these insight, we conclude that (1) except the known 1C targets (DHFR, GART, and TYMS), MTHFD2 emerges as good drug target, especially for treating hematopoietic cancers such as CLL, AML, and T-cell lymphoma; (2) SHMT2 and MTHFD1L are potential drug targets; and (3) MTHFD2L and ALDH1L2 should not be considered as drug targets. We highlight MTHFD2 as an excellent therapeutic target and SHMT2 as a complementary target based on structural/biochemical considerations and up-to-date inhibitor development, which underscores the perspectives of their therapeutic potential.

Amomum subulatum Induces Apoptosis in Tumor Cells and Reduces Tumor Burden in Experimental Animals via Modulating Pro-Inflammatory Cytokines.

This study investigates the anticancer potential of methanolic extract of A. subulatum dry fruits (MEAS) in Dalton's Lymphoma Ascites (DLA) cells in vitro and on DLA induced ascitic and solid tumor-bearing mice. MEAS induced apoptosis in DLA cells and MEAS administration effectively reduced tumor burden, and increased life span via modulating pro-inflammatory cytokines and regulating NF-κB pathway. MEAS seemed to be much safer than the standard drug cyclophosphamide, as the latter was associated with adverse effects such as body weight loss, depletion of hemoglobin level and hepatotoxicity, suggesting A. subulatum as a potential nutraceutical against cancer.

Phenothiazines and Selenocompounds: A Potential Novel Combination Therapy of Multidrug Resistant Cancer.

BACKGROUND/AIM: Phenothiazines constitute a versatile family of compounds in terms of biological activity, which have also gained a considerable attention in cancer research. MATERIALS AND METHODS: Three phenothiazines (promethazine, chlorpromazine and thioridazine) have been tested in combination with 11 active selenocompounds against MDR (ABCB1-overexpressing) mouse T-lymphoma cells to investigate their activity as combination chemotherapy and as antitumor adjuvants in vitro with a checkerboard combination assay. RESULTS: Seven selenocompounds showed toxicity on mouse embryonic fibroblasts, while three showed selectivity towards tumor cells. Two compounds showed synergism with all tested phenothiazines in low concentration ranges (1.46-11.25 µM). Thioridazine was the most potent among the three phenothiazines. CONCLUSION: Phenothiazines belonging to different generations showed different levels of adjuvant activities. All the tested phenothiazines are already approved medicines with known pharmacological and toxicity profiles, therefore, their use as adjuvants in cancer may be considered as a potential drug repurposing strategy.

[Leucovorin Administration Allows Continued Pralatrexate Treatment in a Patient with Angioimmunoblastic T-Cell Lymphoma].

Pralatrexate(PDX)has been approved for the treatment of relapsed/refractory peripheral T-cell lymphoma(PTCL), including angioimmunoblastic T-cell lymphoma(AITL). Oral mucositis is the most common and severe adverse effect of PDX that often leads to dose reduction or omission. Herein, we report a 65-year-old man with AITL, who received PDX treatment after a second relapse. This drug was effective; however, the adverse effects, such as oral mucositis, were severe. Therefore, leucovorin(LV)was administered to prevent the adverse effect, resulting in continuation of the PDX treatment for 8 months. LV administration minimizes adverse effects for patients receiving high-dose methotrexate. However, the optimal dose and schedule of LV in PDX treatment has not yet been established. In the future, clinical trials on the use of LV for PDX-induced oral mucositis are needed.

Associations of environment, health history, T-zone lymphoma, and T-zone-like cells of undetermined significance: A case-control study of aged Golden Retrievers.

BACKGROUND: T-zone lymphoma (TZL), an indolent disease in older dogs, comprises approximately 12% of lymphomas in dogs. TZL cells exhibit an activated phenotype, indicating the disease may be antigen-driven. Prior research found that asymptomatic aged Golden Retrievers (GLDRs) commonly have populations of T-zone-like cells (phenotypically identical to TZL) of undetermined significance (TZUS). OBJECTIVE: To evaluate associations of inflammatory conditions, TZL and TZUS, using a case-control study of GLDRs. ANIMALS: TZL cases (n = 140), flow cytometrically diagnosed, were identified through Colorado State University's Clinical Immunology Laboratory. Non-TZL dogs, recruited through either a database of owners interested in research participation or the submitting clinics of TZL cases, were subsequently flow cytometrically classified as TZUS (n = 221) or control (n = 147). METHODS: Health history, signalment, environmental, and lifestyle factors were obtained from owner-completed questionnaires. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated using multivariable logistic regression, obtaining separate estimates for TZL and TZUS (versus controls). RESULTS: Hypothyroidism (OR, 0.3; 95% CI, 0.1-0.7), omega-3 supplementation (OR, 0.3; 95% CI, 0.1-0.6), and mange (OR, 5.5; 95% CI, 1.4-21.1) were significantly associated with TZL. Gastrointestinal disease (OR, 2.4; 95% CI, 0.98-5.8) had nonsignificantly increased TZL odds. Two shared associations for TZL and TZUS were identified: bladder infection or calculi (TZL OR, 3.5; 95% CI, 0.96-12.7; TZUS OR, 5.1; 95% CI, 1.9-13.7) and eye disease (TZL OR, 2.3; 95% CI, 0.97-5.2; TZUS OR, 1.9; 95% CI, 0.99-3.8). CONCLUSIONS AND CLINICAL IMPORTANCE: These findings may elucidate pathways involved in TZUS risk and progression from TZUS to TZL. Further investigation into the protective association of omega-3 supplements is warranted.

Necrotizing Granulomatous Dermatitis and Panniculitis Masquerading as T Cell Lymphoma.

A 51-year-old white woman with a past medical history significant for steroid-dependent ulcerative colitis, rheumatoid arthritis, and diabetes mellitus presented to the hospital with fever and painful, erythematous subcutaneous nodules on the medical aspects of both thighs. Histopathologic examination showed features suggestive of an abscess, but her condition failed to improve with intravenous broad-spectrum antibiotics. Molecular studies detected T cell receptor-ß gene rearrangements. The lesions later exhibited signs of necrosis, requiring multiple debridements as well as therapy with hyperbaric oxygen. She was later referred to the MD Anderson Cancer Center for evaluation for possible subcutaneous panniculitis-like T cell lymphoma.

Exocyclic Sulfur and Selenoorganic Compounds Towards Their Anticancer Effects: Crystallographic and Biological Studies.

BACKGROUND/AIM: Multidrug resistance leads to therapeutic difficulties. There is great interest in experimental chemotherapy regarding multidrug resistance inhibitors and new anticancer agents. The aim of this study was to evaluate the anticancer activity of exocyclic sulfur and selenoorganic compounds on mouse T-lymphoma cell lines. MATERIALS AND METHODS: A series of eighteen sulfur and selenium analogues of 2[1H]-pyrimidinone and hydantoin derivatives were evaluated towards their efflux modulating, cytotoxic and antiproliferative effects in mouse T-lymphoma cells. The combination assay with doxorubicin on multidrug resistant mouse T-lymphoma cells was performed in order to see the nature of drug interactions. Crystal structures were determined for two selected compounds with the highest efflux-modulating activity. RESULTS: The sulfur analogues with aromatic rings almost perpendicular to pyrimidinethione ring at positions 1 and 6 showed the highest efflux inhibitory action, while all selenium analogues showed good antiproliferative and cytotoxic activities. CONCLUSION: The sulfur analogues can be modified towards improving their efflux inhibitory activity, whereas the selenium towards antiproliferative and cytotoxic activities.

Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models.

T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs). We show that MDM2 and MDMX are targetable vulnerabilities within TP53-wild-type TCLs. ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin. ALRN-6924 induced a complete remission in a patient with TP53-wild-type angioimmunoblastic T-cell lymphoma, demonstrating the potential for rapid translation of discoveries from subtype-specific preclinical models.

The discovery and development of romidepsin for the treatment of T-cell lymphoma.

INTRODUCTION: Romidepsin is a potent and selective inhibitor of histone deacetylases (HDCAi). It is also the only bicyclic inhibitor to undergo clinical assessment and is considered a promising drug for the treatment of T-cell lymphomas. The cellular action of romidepsin results in enhanced histone acetylation, as well as the acetylation of other nuclear or cytoplasmic proteins, influencing cell cycle, apoptosis, and angiogenesis. In phase II studies involving patients with relapsed or refractory of cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), romidepsin produced overall response rates (ORR) of 34-35% and 25-38%, with complete response (CR) rates of 6% and 15-18%, respectively. Areas covered: This review summarizes the development of romidepsin, the mechanisms behind its antineoplastic action and its pharmacology. It also covers its pharmacokinetic and pharmacodynamic properties, as well as the preclinical and clinical data on its activity in T-cell lymphoma. Expert opinion: Since there are only few effective therapies available for T-cell lymphomas, romidepsin is a valuable option for relapsed/refractory patients with both CTCL and PTCL. It's also generally well tolerated, and gives potentially durable responses for patients with advanced and symptomatic disease. Combinations of romidepsin with other antineoplastic agents may also further improve drug response and outcomes in T-cell lymphoma.

Dregamine and tabernaemontanine derivatives as ABCB1 modulators on resistant cancer cells.

Dregamine (1) and tabernaemontanine (2), two epimeric monoterpene indole alkaloids isolated in large amount from the roots of the African plant Tabernaemontana elegans, were derivatized, yielding ten imine derivatives, as previously described (3-12). In the present study, aiming at increasing the pool of analogues for establishing structure-activity relationships (SAR), compounds 1 and 2 were further submitted to several chemical transformations, yielding thirteen new derivatives (13-25). Their structures were assigned by spectroscopic methods, including 1D and 2D NMR experiments. Compounds 1-25 were evaluated for their effects on the reversion of multidrug resistance (MDR) in cancer cells mediated by P-glycoprotein (P-gp/ABCB1), through combination of functional and chemosensitivity assays, using a human ABCB1-transfected mouse T-lymphoma cell model. SAR analysis showed that different substituents at C-3 and at the indole nitrogen led to different ABCB1 modulatory effects. When compared to the parent compounds, a remarkable enhancement in MDR reversal activity was found for derivatives sharing a new aromatic moiety. Thus, the strongest ability as MDR reversers, and a manifold activity when compared to verapamil, was found for compound 8, the epimeric compounds 9 and 10, and compound 15, bearing pyrazine, bromo-pyridine, and methoxybenzyloxycarbonyl moieties, respectively. In drug combination assays, all compounds tested were revealed to interact synergistically with doxorubicin. Collectively, the results indicate that some of these derivatives may be promising leads for overcoming MDR in cancer.

Iron chelation: an adjuvant therapy to target metabolism, growth and survival of murine PTEN-deficient T lymphoma and human T lymphoblastic leukemia/lymphoma.

Iron is an essential nutrient, acting as a catalyst for metabolic reactions that are fundamental to cell survival and proliferation. Iron complexed to transferrin is delivered to the metabolism after endocytosis via the CD71 surface receptor. We found that transformed cells from a murine PTEN-deficient T-cell lymphoma model and from T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LL) cell lines overexpress CD71. As a consequence, the cells developed an addiction toward iron whose chelation by deferoxamine (DFO) dramatically affected their survival to induce apoptosis. Interestingly, DFO displayed synergistic activity with three ALL-specific drugs: dexamethasone, doxorubicin, and L-asparaginase. DFO appeared to act through a reactive oxygen species-dependent DNA damage response and potentiated the action of an inhibitor of the PARP pathway of DNA repair. Our results demonstrate that targeting iron metabolism could be an interesting adjuvant therapy for acute lymphoblastic leukemia.

PI-103 and Quercetin Attenuate PI3K-AKT Signaling Pathway in T- Cell Lymphoma Exposed to Hydrogen Peroxide.

Phosphatidylinositol 3 kinase-protein kinase B (PI3K-AKT) pathway has been considered as major drug target site due to its frequent activation in cancer. AKT regulates the activity of various targets to promote tumorigenesis and metastasis. Accumulation of reactive oxygen species (ROS) has been linked to oxidative stress and regulation of signaling pathways for metabolic adaptation of tumor microenvironment. Hydrogen peroxide (H2O2) in this context is used as ROS source for oxidative stress preconditioning. Antioxidants are commonly considered to be beneficial to reduce detrimental effects of ROS and are recommended as dietary supplements. Quercetin, a ubiquitous bioactive flavonoid is a dietary component which has attracted much of interest due to its potential health-promoting effects. Present study is aimed to analyze PI3K-AKT signaling pathway in H2O2 exposed Dalton's lymphoma ascite (DLA) cells. Further, regulation of PI3K-AKT pathway by quercetin as well as PI-103, an inhibitor of PI3K was analyzed. Exposure of H2O2 (1mM H2O2 for 30min) to DLA cells caused ROS accumulation and resulted in increased phosphorylation of PI3K and downstream proteins PDK1 and AKT (Ser-473 and Thr-308), cell survival factors BAD and ERK1/2, as well as TNFR1. However, level of tumor suppressor PTEN was declined. Both PI-103 & quercetin suppressed the enhanced level of ROS and significantly down-regulated phosphorylation of AKT, PDK1, BAD and level of TNFR1 as well as increased the level of PTEN in H2O2 induced lymphoma cells. The overall result suggests that quercetin and PI3K inhibitor PI-103 attenuate PI3K-AKT pathway in a similar mechanism.