Impact of electronic cigarettes on pediatric, adolescent and young adult leukemia patients.

Electronic cigarettes, which deliver an aerosolized, nicotine-containing product upon inhalation, are a public health issue that continue to gain popularity among adolescents and young adults in the United States. Use of electronic cigarettes is wide, and extends to pediatric patients with multiple comorbidities, including childhood cancer, leaving them vulnerable to further negative health outcomes. Acute leukemias are the most common type of cancer in pediatric populations, and treatment outcomes for these patients are improving; consequently, there is an increased emphasis on the effect of behavioral lifestyle factors on quality of life in survivorship. The rate of electronic cigarette use is higher among pediatric patients with a history of cancer than those without a history of cancer. Because electronic cigarettes are relatively new, much about their acute and long-term consequences remains unknown, as is their effect on therapy outcomes and long-term survivorship. This review article summarizes current knowledge about electronic cigarettes, including their composition and the trends in use among pediatric patients. Furthermore, this review provides a comprehensive description of the impact electronic cigarettes have on leukemia development, treatment and survivorship and highlights gaps in knowledge that will be necessary for developing recommendations, management strategies, and tailored treatments for pediatric leukemia patients and survivors who use these nicotine products.

Case series: Stenotrophomonas maltophilia in pediatric oncology patients.

BACKGROUND: Stenotrophomonas maltophilia is a bacterial pathogen that can be fatal in hospitalized and immunocompromised patients with mortality as high as 69%. Pediatric cancer patients often have risk factors that are common for this infection, making them particularly susceptible. Managing S. maltophilia is especially challenging as it has inherent resistance to several antibiotics. Furthermore, soft tissue infections in neutropenic patients may deviate from the typical clinical presentation of S. maltophilia. CASE DETAILS: This case series describes an in-depth examination of three cases involving immunocompromised pediatric patients with S. maltophilia infections. Each case exhibited a distinct clinical presentation, encompassing infection of the blood, lung, and skin, which highlights the variability in which S. maltophilia manifests in immunocompromised pediatric patients. These patients were treated at MD Anderson Cancer Center (MDACC) from 2020 to 2023, unfortunately resulting in fatality. CONCLUSIONS: The study aims to provide valuable insights and guidance for the management of patients with S. maltophilia infections. Emphasizing a heightened clinical suspicion will potentially lead to early initiation of directed therapy against S. maltophilia. Timely intervention may play a pivotal role in improving patient outcomes and reduce further burden to the healthcare system.

Renal Cell Carcinoma Unclassified with Medullary Phenotype in a Patient with Neurofibromatosis Type 2.

We present, to our knowledge, the first reported case of germline neurofibromatosis Type 2 (NF2) associated with renal cell carcinoma unclassified with medullary phenotype (RCCU-MP) with somatic loss by immunohistochemistry of the SMARCB1 tumor suppressor gene located centromeric to NF2 on chromosome 22q. Our patient is a 15-year-old with germline neurofibromatosis Type 2 (NF2) confirmed by pathogenic mutation of c.-854-??46+??deletion. Her NF2 history is positive for a right optic nerve sheath meningioma, CNIII schwannoma requiring radiation therapy and post gross total resection of right frontotemporal anaplastic meningioma followed by radiation. At age 15 she developed new onset weight loss and abdominal pain due to RCCU-MP. Hemoglobin electrophoresis was negative for sickle hemoglobinopathy. Chemotherapy (cisplatin, gemcitabine and paclitaxel) was initiated followed by radical resection. Given the unique renal pathology of a high grade malignancy with loss of SMARCB1 expression via immunohistochemistry, and history of meningioma with MLH1 loss of expression and retained expression of PMS2, MSH2 and MSH6, further germline genetic testing was sent for SMARCB1 and mismatch repair syndromes. Germline testing was negative for mutation in SMARCB1. Therefore, this is the first reported case of RCCU-MP associated with germline NF2 mutation. This suggests the importance of closer surveillance in the adolescent and young adult population with NF2 with any suspicious findings of malignancy outside of the usual scope of practice with NF2.

Anticancer action of garcinol in vitro and in vivo is in part mediated through inhibition of STAT-3 signaling.

Garcinol, obtained from Garcinia indica, has exhibited some promising anticancer activity. In particular, our earlier work has demonstrated its ability to inhibit cell proliferation and induction of apoptosis in multiple cancer cell lines representative of breast, prostate, as well as pancreatic cancers. However, its exact mechanism of action remains largely unclear. Here we show that garcinol also targets signal transducer and activator of transcription-3 (STAT-3) signaling pathway. STAT-3 is frequently found to be activated in many cancer types and this is the first report on such action of garcinol leading to its anticancer effects. Garcinol inhibited total, as well as phosphorylated, STAT-3 in breast, prostate and pancreatic cancer cell lines and was also found to inhibit cell invasion of all the cancer cell lines tested. STAT-3 phosphorylation was inhibited by garcinol in a dose-dependent manner. We also observed an inhibitory effect of garcinol on IL-6-induced STAT-3 phosphorylation and production of urokinase-type plasminogen activator, vascular endothelial growth factor and matrix metalloproteinase-9, which might explain the reduced invasion and aggressiveness of cells treated with garcinol. The results were further verified in vivo using MDA-MB-231 breast cancer mouse xenograft model where administration of garcinol significantly inhibited tumor growth, and western blot analysis of remnant tumor lysates showed reduced STAT-3 expression and activation. These results suggest that garcinol may have translational potential as chemopreventive or therapeutic agent against multiple cancers and inhibition of STAT-3 signaling pathway is one of the mechanisms by which garcinol exerts its anticancer effects.

Garcinol regulates EMT and Wnt signaling pathways in vitro and in vivo, leading to anticancer activity against breast cancer cells.

Anticancer properties of Garcinia indica-derived garcinol are just beginning to be elucidated. We have earlier reported its cancer cell-specific induction of apoptosis in breast cancer cells, which was mediated through the downregulation of NF-κB signaling pathway. To gain further mechanistic insight, here, we show for the first time that garcinol effectively reverses epithelial-to-mesenchymal transition (EMT), that is, it induces mesenchymal-to-epithelial transition (MET) in aggressive triple-negative MDA-MB-231 and BT-549 breast cancer cells. This was associated with upregulation of epithelial marker E-cadherin and downregulation of mesenchymal markers vimentin, ZEB-1, and ZEB-2. We also found that garcinol upregulates the expression of miR-200 and let-7 family microRNAs (miRNAs), which provides a molecular mechanism for the observed reversal of EMT to MET. Transfection of cells with NF-κB p65 subunit attenuated the effect of garcinol on apoptosis induction through reversal of MET to EMT. Forced transfection of p65 and anti-miR-200s could also reverse the inhibitory effect of garcinol on breast cancer cell invasion. Moreover, treatment with garcinol resulted in increased phosphorylation of ß-catenin concomitant with its reduced nuclear localization. The results were also validated in vivo in a xenograft mouse model where garcinol was found to inhibit NF-κB, miRNAs, vimentin, and nuclear ß-catenin. These novel findings suggest that the anticancer activity of garcinol against aggressive breast cancer cells is, in part, due to reversal of EMT phenotype, which is mechanistically linked with the deregulation of miR-200s, let-7s, NF-κB, and Wnt signaling pathways.

A Th1 cytokine-enriched microenvironment enhances tumor killing by activated T cells armed with bispecific antibodies and inhibits the development of myeloid-derived suppressor cells.

In this study, we investigated whether activated T cells (ATC) armed with bispecific antibodies (aATC) can inhibits tumor growth and MDSC development in a Th1 cytokine-enriched (IL-2 and IFN-γ) microenvironment. Cytotoxicity mediated by aATC was significantly higher (P < 0.001) against breast cancer cell lines in the presence of Th1 cytokines as compared with control co-cultures. In the presence of aATC, CD33+ /CD11b+ /CD14- /HLA-DR- MDSC population was reduced significantly under both control (P < 0.03) and Th1-enriched (P < 0.036) culture conditions. Cytokine analysis in the culture supernatants showed high levels of MDSC suppressive chemokines CXCL9 and CXCL10 in Th1-enriched culture supernatants with highly significant increase (P < 0.001) in the presence of aATC. Interestingly, MDSC recovered from co-cultures without aATC showed potent ability to suppress activated T-cell-mediated cytotoxicity (P < 0.001), IFN-γ production (P < 0.01) and T-cell proliferation (P < 0.05) compared to those recovered from aATC-containing co-cultures. These data suggest that aATC can mediate enhanced killing of tumor cells and may suppress MDSC and T(reg) differentiation, and presence of Th() cytokines potentiates aATC-induced suppression of MDSC, suggesting that Th1-enriching immunotherapy may be beneficial in cancer treatment.

Metformin inhibits cell proliferation, migration and invasion by attenuating CSC function mediated by deregulating miRNAs in pancreatic cancer cells.

Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States, which is, in part, due to intrinsic (de novo) and extrinsic (acquired) resistance to conventional therapeutics, suggesting that innovative treatment strategies are required for overcoming therapeutic resistance to improve overall survival of patients. Oral administration of metformin in patients with diabetes mellitus has been reported to be associated with reduced risk of pancreatic cancer and that metformin has been reported to kill cancer stem cells (CSC); however, the exact molecular mechanism(s) has not been fully elucidated. In the current study, we examined the effect of metformin on cell proliferation, cell migration and invasion, and self-renewal capacity of CSCs and further assessed the expression of CSC marker genes and microRNAs (miRNA) in human pancreatic cancer cells. We found that metformin significantly decreased cell survival, clonogenicity, wound-healing capacity, sphere-forming capacity (pancreatospheres), and increased disintegration of pancreatospheres in both gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cells. Metformin also decreased the expression of CSC markers,CD44, EpCAM,EZH2, Notch-1, Nanog and Oct4, and caused reexpression of miRNAs (let-7a,let-7b, miR-26a, miR-101, miR-200b, and miR-200c) that are typically lost in pancreatic cancer and especially in pancreatospheres. We also found that reexpression of miR-26a by transfection led to decreased expression of EZH2 and EpCAM in pancreatic cancer cells. These results clearly suggest that the biologic effects of metformin are mediated through reexpression of miRNAs and decreased expression of CSC-specific genes, suggesting that metformin could be useful for overcoming therapeutic resistance of pancreatic cancer cells.

Anti-tumor activity of a novel compound-CDF is mediated by regulating miR-21, miR-200, and PTEN in pancreatic cancer.

BACKGROUND: The existence of cancer stem cells (CSCs) or cancer stem-like cells in a tumor mass is believed to be responsible for tumor recurrence because of their intrinsic and extrinsic drug-resistance characteristics. Therefore, targeted killing of CSCs would be a newer strategy for the prevention of tumor recurrence and/or treatment by overcoming drug-resistance. We have developed a novel synthetic compound-CDF, which showed greater bioavailability in animal tissues such as pancreas, and also induced cell growth inhibition and apoptosis, which was mediated by inactivation of NF-κB, COX-2, and VEGF in pancreatic cancer (PC) cells. METHODOLOGY/PRINCIPAL FINDINGS: In the current study we showed, for the first time, that CDF could significantly inhibit the sphere-forming ability (pancreatospheres) of PC cells consistent with increased disintegration of pancreatospheres, which was associated with attenuation of CSC markers (CD44 and EpCAM), especially in gemcitabine-resistant (MIAPaCa-2) PC cells containing high proportion of CSCs consistent with increased miR-21 and decreased miR-200. In a xenograft mouse model of human PC, CDF treatment significantly inhibited tumor growth, which was associated with decreased NF-κB DNA binding activity, COX-2, and miR-21 expression, and increased PTEN and miR-200 expression in tumor remnants. CONCLUSIONS/SIGNIFICANCE: These results strongly suggest that the anti-tumor activity of CDF is associated with inhibition of CSC function via down-regulation of CSC-associated signaling pathways. Therefore, CDF could be useful for the prevention of tumor recurrence and/or treatment of PC with better treatment outcome in the future.

Down-regulation of uPA and uPAR by 3,3'-diindolylmethane contributes to the inhibition of cell growth and migration of breast cancer cells.

3,3'-Diindolylmethane (DIM) is a known anti-tumor agent against breast and other cancers; however, its exact mechanism of action remains unclear. The urokinase plasminogen activator (uPA) and its receptor (uPAR) system are involved in the degradation of basement membrane and extracellular matrix, leading to tumor cell invasion and metastasis. Since uPA-uPAR system is highly activated in aggressive breast cancer, we hypothesized that the biological activity of B-DIM could be mediated via inactivation of uPA-uPAR system. We found that B-DIM treatment as well as silencing of uPA-uPAR led to the inhibition of cell growth and motility of MDA-MB-231 cells, which was in part due to inhibition of VEGF and MMP-9. Moreover, silencing of uPA-uPAR led to decreased sensitivity of these cells to B-DIM indicating an important role of uPA-uPAR in B-DIM-mediated inhibition of cell growth and migration. We also found similar effects of B-DIM on MCF-7, cells expressing low levels of uPA-uPAR, which was due to direct down-regulation of MMP-9 and VEGF, independent of uPA-uPAR system. Interestingly, over-expression of uPA-uPAR in MCF-7 cells attenuated the inhibitory effects of B-DIM. Our results, therefore, suggest that B-DIM down-regulates uPA-uPAR in aggressive breast cancers but in the absence of uPA-uPAR, B-DIM can directly inhibit VEGF and MMP-9 leading to the inhibition of cell growth and migration of breast cancer cells.

Inactivation of uPA and its receptor uPAR by 3,3'-diindolylmethane (DIM) leads to the inhibition of prostate cancer cell growth and migration.

3,3'-Diindolylmethane (DIM) has been studied for its putative anti-cancer properties, especially against prostate cancer; however, its exact mechanism of action remains unclear. We recently provided preliminary data suggesting down-regulation of uPA during B-DIM (a clinically active DIM)-induced inhibition of invasion and angiogenesis in prostate cancer cells. Since the expression and activation of uPA plays important role in tumorigenicity, and high endogenous levels of uPA and uPAR are found in advanced metastatic cancers, we investigated their role in B-DIM-mediated inhibition of prostate cancer cell growth and motility. Using PC3 cells, we found that B-DIM treatment as well as the silencing of uPA and uPAR by siRNAs led to the inhibition of cell growth and motility. Conversely, over-expression of uPA/uPAR in LNCaP and C4-2B cells resulted in increased cell growth and motility, which was effectively inhibited by B-DIM. Moreover, we found that uPA as well as uPAR induced the production of VEGF and MMP-9, and that the down-regulation of uPA/uPAR by siRNAs or B-DIM treatment resulted in the inhibition of VEGF and MMP-9 secretion which could be responsible for the observed inhibition of cell migration. Interestingly, silencing of uPA/uPAR led to decreased sensitivity to B-DIM indicating important role of uPA/uPAR in B-DIM-mediated regulation of prostate cancer cell growth and migration. Our data suggest that chemopreventive and/or therapeutic activity of B-DIM is in part due to down-regulation of uPA-uPAR leading to reduced production of VEGF/MMP-9 which ultimately leads to the inhibition of cell growth and migration of aggressive prostate cancer cells.

Regulation of Akt/FOXO3a/GSK-3beta/AR signaling network by isoflavone in prostate cancer cells.

We have previously shown that genistein could inhibit Akt activation and down-regulate AR (androgen receptor) and PSA (prostate-specific antigen) expression in prostate cancer (PCa) cells. However, pure genistein showed increased lymph node metastasis in an animal model, but such an adverse effect was not seen with isoflavone, suggesting that further mechanistic studies are needed for elucidating the role of isoflavone in PCa. It is known that FOXO3a and GSK-3beta, targets of Akt, regulate cell proliferation and apoptosis. Moreover, FOXO3a, GSK-3beta, and Src are AR regulators and regulate transactivation of AR, mediating the development and progression of PCa. Therefore, we investigated the molecular effects of isoflavone on the Akt/FOXO3a/GSK-3beta/AR signaling network in hormone-sensitive LNCaP and hormone-insensitive C4-2B PCa cells. We found that isoflavone inhibited the phosphorylation of Akt and FOXO3a, regulated the phosphorylation of Src, and increased the expression of GSK-3beta, leading to the down-regulation of AR and its target gene PSA. We also found that isoflavone inhibited AR nuclear translocation and promoted FOXO3a translocation to the nucleus. By electrophoretic mobility shift assay and chromatin immunoprecipitation assay, we found that isoflavone inhibited FOXO3a binding to the promoter of AR and increased FOXO3a binding to the p27(KIP1) promoter, resulting in the alteration of AR and p27(KIP1) expression, the inhibition of cell proliferation, and the induction of apoptosis in both androgen-sensitive and -insensitive PCa cells. These results suggest that isoflavone-induced inhibition of cell proliferation and induction of apoptosis are partly mediated through the regulation of the Akt/FOXO3a/GSK-3beta/AR signaling network. In conclusion, our data suggest that isoflavone could be useful for the prevention and/or treatment of PCa.

Inactivation of NF-kappaB by 3,3'-diindolylmethane contributes to increased apoptosis induced by chemotherapeutic agent in breast cancer cells.

Constitutive activation of Akt or nuclear factor-kappaB (NF-kappaB) has been reported to play a role in de novo resistance of cancer cells to chemotherapeutic agents, which is a major cause of treatment failure in cancer chemotherapy. Previous studies have shown that 3,3'-diindolylmethane (DIM), a major in vivo acid-catalyzed condensation product of indole-3-carbinol, is a potent inducer of apoptosis, inhibitor of tumor angiogenesis, and inactivator of Akt/NF-kappaB signaling in breast cancer cells. However, little is known regarding the inactivation of Akt/NF-kappaB that leads to chemosensitization of breast cancer cells to chemotherapeutic agents, such as Taxotere. Therefore, we examined whether the inactivation Akt/NF-kappaB signaling caused by B-DIM could sensitize breast cancer cells to chemotherapeutic agents both in vitro and in vivo. MDA-MB-231 cells were simultaneously treated with 15 to 45 micromol/L B-DIM and 0.5 to 1.0 nmol/L Taxotere for 24 to 72 h. Cell growth inhibition assay, apoptosis assay, electrophoretic mobility shift assay, and Western blotting were done. The combination treatment of 30 micromol/L B-DIM with 1.0 nmol/L Taxotere elicited significantly greater inhibition of cell growth compared with either agent alone. The combination treatment induced greater apoptosis in MDA-MB-231 cells compared with single agents. Moreover, we found that NF-kappaB activity was significantly decreased in cells treated with B-DIM and Taxotere. We also have tested our hypothesis using transfection studies, followed by combination treatment with B-DIM/Taxotere, and found that combination treatment significantly inhibited cell growth and induced apoptosis in MDA-MB-231 breast cancer cells mediated by the inactivation of NF-kappaB, a specific target in vitro and in vivo. These results were also supported by animal experiments, which clearly showed that B-DIM sensitized the breast tumors to Taxotere, which resulted in greater antitumor activity mediated by the inhibition of Akt and NF-kappaB. Collectively, our results clearly suggest that inhibition of Akt/NF-kappaB signaling by B-DIM leads to chemosensitization of breast cancer cells to Taxotere, which may contribute to increased growth inhibition and apoptosis in breast cancer cells. The data obtained from our studies could be a novel breakthrough in cancer therapeutics by using nontoxic agents, such as B-DIM, in combination with other conventional therapeutic agents, such as Taxotere.