A novel ruthenium complex with 5-fluorouracil suppresses colorectal cancer stem cells by inhibiting Akt/mTOR signaling.

[Ru(5-FU)(PPh3)2(bipy)]PF6 (Ru/5-FU) is a novel ruthenium complex with 5-fluorouracil with promising potential against colorectal cancer (CRC). In the present study, we investigated the molecular mechanism of Ru/5-FU action in HCT116 CRC cells. Ru/5-FU exhibited potent cytotoxicity on a panel of cancer cell lines and on primary cancer cells and induced apoptosis in HCT116 CRC cells. Ru/5-FU reduced AKT1 gene transcripts, as well as the expression of Akt1 and Akt (pS473) and downstream Akt proteins mTOR (pS2448), S6 (pS235/pS236), 4EBP1 (pT36/pT45), GSK-3ß (pS9) and NF-κB p65 (pS529), but not Akt upstream proteins Hsp90 and PI3K p85/p55 (pT458/pT199), indicating an inhibitory action of Akt/mTOR signaling. Ru/5-FU increased LC3B expression and reduced p62/SQSTM1 levels, indicating autophagy induction. Curiously, the autophagy inhibitors 3-methyladenine and chloroquine increased Ru/5-FU-induced cell death, indicating an induction of cytoprotective autophagy by this compound. Ru/5-FU also reduced clonogenic survival, as well as the percentage of CD133+ cells and colonosphere formation, indicating that Ru/5-FU can suppress stem cells in HCT116 cells. Ru/5-FU inhibited cell migration and invasion in wound healing assays and Transwell cell invasion assays, along with a reduction in vimentin expression and an increase in E-cadherin levels, indicating that Ru/5-FU can interfere with epithelial-mesenchymal transition. Ru/5-FU also inhibited in vivo HCT116 cell development and experimental lung metastases in mouse xenograft models. Altogether, these results indicate that Ru/5-FU is an anti-CRC chemotherapy drug candidate with the ability to suppress stemness in CRC cells by inhibiting Akt/mTOR signaling.

New ruthenium-xanthoxylin complex eliminates colorectal cancer stem cells by targeting the heat shock protein 90 chaperone.

In this work, we describe a novel ruthenium-xanthoxylin complex, [Ru(phen)2(xant)](PF6) (RXC), that can eliminate colorectal cancer (CRC) stem cells by targeting the chaperone Hsp90. RXC exhibits potent cytotoxicity in cancer cell lines and primary cancer cells, causing apoptosis in HCT116 CRC cells, as observed by cell morphology, YO-PRO-1/PI staining, internucleosomal DNA fragmentation, mitochondrial depolarization, and PARP cleavage (Asp214). Additionally, RXC can downregulate the HSP90AA1 and HSP90B1 genes and the expression of HSP90 protein, as well as the expression levels of its downstream/client elements Akt1, Akt (pS473), mTOR (pS2448), 4EBP1 (pT36/pT45), GSK-3ß (pS9), and NF-κB p65 (pS529), implying that these molecular chaperones can be molecular targets for RXC. Moreover, this compound inhibited clonogenic survival, the percentage of the CRC stem cell subpopulation, and colonosphere formation, indicating that RXC can eliminate CRC stem cells. RXC reduced cell migration and invasion, decreased vimentin and increased E-cadherin expression, and induced an autophagic process that appeared to be cytoprotective, as autophagy inhibitors enhanced RXC-induced cell death. In vivo studies showed that RXC inhibits tumor progression and experimental metastasis in mice with CRC HCT116 cell xenografts. Taken together, these results highlight the potential of the ruthenium complex RXC in CRC therapy with the ability to eliminate CRC stem cells by targeting the chaperone Hsp90.

Emerging agents that target signaling pathways to eradicate colorectal cancer stem cells.

Colorectal cancer (CRC) represents the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide. The modern concept of cancer biology indicates that cancer is formed of a small population of cells called cancer stem cells (CSCs), which present both pluripotency and self-renewal properties. These cells are considered responsible for the progression of the disease, recurrence and tumor resistance. Interestingly, some cell signaling pathways participate in CRC survival, proliferation, and self-renewal properties, and most of them are dysregulated in CSCs, including the Wingless (Wnt)/ß-catenin, Notch, Hedgehog, nuclear factor kappa B (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), peroxisome proliferator-activated receptor (PPAR), phosphatidyl-inositol-3-kinase/Akt/mechanistic target of rapamycin (PI3K/Akt/mTOR), and transforming growth factor-ß (TGF-ß)/Smad pathways. In this review, we summarize the strategies for eradicating CRC stem cells by modulating these dysregulated pathways, which will contribute to the study of potential therapeutic schemes, combining conventional drugs with CSC-targeting drugs, and allowing better cure rates in anti-CRC therapy.

The impact of PRODIGE 7 on the current worldwide practice of CRS-HIPEC for colorectal peritoneal metastases: A web-based survey and 2021 statement by Peritoneal Surface Oncology Group International (PSOGI).

INTRODUCTION: The PRODIGE 7-trial investigated the additional value of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) to cytoreductive surgery (CRS) for patients with colorectal peritoneal metastases (CPM). The results of PRODIGE 7 were presented at the 2018 ASCO meeting showing that 30 min oxaliplatin-based HIPEC did not improve overall survival. The current study investigated the impact of PRODIGE 7 on the worldwide practice of CRS and HIPEC. MATERIALS AND METHODS: CRS-HIPEC experts from 19 countries were invited through the Peritoneal Surface Oncology Group International (PSOGI) to complete an online survey concerning the current CRS-HIPEC practice in their hospital and country, and were asked to appraise the effect of PRODIGE 7. RESULTS: The survey was completed by 18/19 experts. Although their personal opinions of CRS-HIPEC were barely influenced by PRODIGE 7, they reported a substantial impact on daily practice. This included a switch towards Mitomycin-C based HIPEC-regimens and prolongation of HIPEC perfusion time, a reduction in the number of referrals from non-HIPEC centers, a reduction in national consensus, the removal of HIPEC from national guidelines, and a reduced reimbursement rate. CONCLUSION: The PRODIGE 7 has had a major impact on the practice of CRS-HIPEC for CPM worldwide. HIPEC remains an attractive option with potential for control and eradication of disease and further studies into the optimal HIPEC-regimen are urgently needed. Meanwhile, given the complexity of the treatment of patients with CPM, and the proven benefits of optimal CRS, referral of patients with potentially resectable CPM to expert centers is recommended whilst the precise role of HIPEC is further evaluated.

Decision-Making Analysis for Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer: A Survey by the Executive Committee of the Peritoneal Surface Oncology Group International (PSOGI).

OBJECTIVES: To assess the individual treatment strategies among international experts in peritoneal carcinosis, specifically their decision-making in the process of patient selection for hyperthermic intraperitoneal chemotherapy (HIPEC) in women suffering from ovarian cancer, to identify relevant decision-making criteria, and to quantify the level of consensus for or against HIPEC. METHODS: The members of the executive committee of the Peritoneal Surface Oncology Group International (PSOGI) were asked to describe the clinical conditions under which they would recommend HIPEC in patients with ovarian cancer and to describe any disease or patient characteristics relevant to their decision. All answers were then merged and converted into decision trees. The decision trees were then analyzed by applying the objective consensus methodology. RESULTS: Nine experts in surgical oncology provided information on their multidisciplinary treatment strategy including HIPEC for patients with advanced ovarian cancer. Three of the total of 12 experts did not perform HIPEC. Five criteria relevant to the decision on whether HIPEC is performed were applied. In patients with resectable disease, a peritoneal cancer index (PCI) <21, and epithelial ovarian cancer without distant metastasis, consent was received by 75% to perform HIPEC for women suffering from recurrent disease. Furthermore, in the primary disease setting, consent was received by 67% to perform HIPEC according to the same criteria. DISCUSSION AND CONCLUSION: Among surgical oncology experts in peritoneal surface malignancy and HIPEC, HIPEC plays an important role in primary and recurrent ovarian cancer, and the PCI is the most important criterion in this decision.

Guidelines of the Brazilian Society of Oncologic Surgery for pelvic exenteration in the treatment of cervical cancer.

BACKGROUND AND OBJECTIVES: The primary treatment for locally advanced cases of cervical cancer is chemoradiation followed by high-dose brachytherapy. When this treatment fails, pelvic exenteration (PE) is an option in some cases. This study aimed to develop recommendations for the best management of patients with cervical cancer undergoing salvage PE. METHODS: A questionnaire was administered to all members of the Brazilian Society of Surgical Oncology. Of them, 68 surgeons participated in the study and were divided into 10 working groups. A literature review of studies retrieved from the National Library of Medicine database was carried out on topics chosen by the participants. These topics were indications for curative and palliative PE, preoperative and intraoperative evaluation of tumor resectability, access routes and surgical techniques, PE classification, urinary, vaginal, intestinal, and pelvic floor reconstructions, and postoperative follow-up. To define the level of evidence and strength of each recommendation, an adapted version of the Infectious Diseases Society of America Health Service rating system was used. RESULTS: Most conducts and management strategies reviewed were strongly recommended by the participants. CONCLUSIONS: Guidelines outlining strategies for PE in the treatment of persistent or relapsed cervical cancer were developed and are based on the best evidence available in the literature.

Suggestion of optimal patient characteristics for sentinel lymph node mapping in colorectal adenocarcinoma / Sugestão de características ideais para a realização de pesquisa de linfonodo sentinela em pacientes com adenocarcinoma colorretal

CONTEXT: In a previously published study, the variables lower rectal tumor site, preoperative chemoradiotherapy and large tumors were considered as independent risk factors for the inability of sentinel lymph node identification in patients with colorectal adenocarcinoma. OBJECTIVES: To determine if these variables could interfere in the precision and upstaging benefit of sentinel lymph node mapping in colorectal cancer. METHODS: A database composed of 52 patients submitted to lymphatic mapping using technetium-99m-phytate and patent blue was reviewed. Only patients with tumors smaller than 5.0 cm, not submitted to preoperative chemoradiotherapy and without lower rectal cancer were included. RESULTS: With these parameters, 11 patients remained to be studied. The sentinel lymph node identification rate was 100 percent, with a sensitivity of 100 percent, negative predictive value of 100 percent, no false negatives and accuracy of 100 percent. Sentinel lymph nodes were the only metastatic nodes in 36.4 percent of the patients, micrometastases (<0.2 cm or only identified by immunohistochemistry) provided an upstaging rate of 27.1 percent and metastases an upstaging rate of 9.1 percent. CONCLUSION: The parameters proposed in this study for selection of colorectal adenocarcinoma patients to be submitted to sentinel lymph node mapping identified optimal accuracy and good upstaging results. As the number of included patients was low, these results could serve as guidance for proper patient selection in further prospective lymph node mapping studies in colorectal cancer patients.

CONTEXTO: As variáveis tumor de reto inferior, quimiorradioterapia pré-operatória e grandes tumores foram considerados fatores de risco independentes para a inabilidade de identificação de linfonodos sentinela em pacientes com adenocarcinoma colorretal. OBJETIVOS: Determinar se essas variáveis poderiam interferir na precisão e no aumento do estádio proporcionado pelo uso da técnica de identificação de linfonodos sentinela em câncer colorretal. Revisão da precisão da técnica do estádio foi realizada. MÉTODOS: O banco de dados composto por 52 pacientes submetidos a mapeamento linfático usando tecnécio-99m-fitato e azul patente foi revisado. Foram incluídos somente pacientes com tumores menores que 5,0 cm, não submetidos a quimiorradioterapia pré-operatória e sem tumores de reto inferior. RESULTADOS: A taxa de identificação de linfonodos sentinela foi de 100 por cento, com sensibilidade de 100 por cento; valor preditivo negativo de 100 por cento, não houve falso-negativos e a precisão foi de 100 por cento. Os linfonodos sentinela foram os únicos linfonodos metastáticos em 36,4 por cento dos pacientes; micrometástases (<0.2 mm ou somente identificadas com imunoistoquímica) proporcionaram taxa de aumento no estádio de 27,1 por cento e metástases taxa de 9,1 por cento. CONCLUSÕES: A validação dos resultados deste estudo deve ser realizada em estudos prospectivos de identificação de linfonodos sentinela que incluam pacientes com câncer colorretal com as características propostas.

Suggestion of optimal patient characteristics for sentinel lymph node mapping in colorectal adenocarcinoma.

CONTEXT: In a previously published study, the variables lower rectal tumor site, preoperative chemoradiotherapy and large tumors were considered as independent risk factors for the inability of sentinel lymph node identification in patients with colorectal adenocarcinoma. OBJECTIVES: To determine if these variables could interfere in the precision and upstaging benefit of sentinel lymph node mapping in colorectal cancer. METHODS: A database composed of 52 patients submitted to lymphatic mapping using technetium-99m-phytate and patent blue was reviewed. Only patients with tumors smaller than 5.0 cm, not submitted to preoperative chemoradiotherapy and without lower rectal cancer were included. RESULTS: With these parameters, 11 patients remained to be studied. The sentinel lymph node identification rate was 100%, with a sensitivity of 100%, negative predictive value of 100%, no false negatives and accuracy of 100%. Sentinel lymph nodes were the only metastatic nodes in 36.4% of the patients, micrometastases (<0.2 cm or only identified by immunohistochemistry) provided an upstaging rate of 27.1% and metastases an upstaging rate of 9.1%. CONCLUSION: The parameters proposed in this study for selection of colorectal adenocarcinoma patients to be submitted to sentinel lymph node mapping identified optimal accuracy and good upstaging results. As the number of included patients was low, these results could serve as guidance for proper patient selection in further prospective lymph node mapping studies in colorectal cancer patients.