The Identification of a Novel Unsymmetrical Azine as an Apoptosis Inducer in Colorectal Cancer.

BACKGROUND: Defects in the physiological mechanisms of apoptosis are one of the pivotal factors implicated in carcinogenesis. Thus, the development of novel compounds that target various apoptotic pathways has provided promising anticancer therapeutic opportunities. OBJECTIVE: This study explores the cytotoxic effects of a novel unsymmetrical azine against specific cancer cell lines and investigates the mechanism of cytotoxicity. METHODS: Molecular modeling was used to test the binding affinity of four new unsymmetrical azines to a model of an apoptosis inhibitor protein (XIAP). The compound with the highest binding affinity, C4, was further tested on different cell lines. Real-time Polymerase Chain Reaction (PCR) and Transmission Electron Microscope (TEM) were used to study apoptosis induction biochemically and morphologically. RESULTS: In comparison to cisplatin as a control, the compound C4 exhibited notable cytotoxicity against all tested cancer cell lines, especially the human colorectal carcinoma cell line (HCT-116). Furthermore, C4-treated cells demonstrated marked overexpression of the pro-apoptotic proteins Bax and caspase-3 as well as the tumor suppressor p53. On the other hand, the expression of the anti-apoptotic protein Bcl-2 was inhibited. On TEM examination, C4-treated HCT-116 cells showed classical structural signs of apoptosis. CONCLUSION: This study identifies a novel azine (C4), which induces remarkable cytotoxicity against the colorectal carcinoma cell line, mediated through apoptosis induction. These novel insights suggest C4 as a promising therapeutic agent in colorectal cancer.

The radiotherapy utilization rate in pediatric tumors: An analysis of 13,305 patients.

PURPOSE: Although the radiotherapy utilization rate (RUR) is determined for most adult cancers, it is seldom reported in childhood tumors, particularly in low- and middle-income countries (LMIC) where the majority of pediatric cancer patients reside. This study aims to investigate the real-life RUR for pediatric tumors in a large LMIC center. MATERIALS AND METHODS: The electronic files of patients treated at a single institution during 2010-2017 were reviewed and the RUR was defined as the percentage of patients who received at least one radiotherapy (RT) course from the total number of patients. RESULTS: A total of 4390 out of 13,305 pediatric cancer patients received at least one RT course with a RUR of 33%. The curative, salvage, and palliative RURs were 27.8%, 2%, and 5.7%, respectively. There was a considerable variation in the RUR between various tumors, ranging from 0% in choroid plexus papilloma and other rare tumors to 100% in intracranial germinoma. Moreover, the RUR varied among different stages within each tumor type. Overall, 753 patients received 920 palliative RT courses (range 1-9) at a median dose of 30 Gy. The most commonly irradiated metastatic sites were the bone (34%) and the brain (9.8%). CONCLUSION: This is the first analysis to provide valuable insights into the RUR for childhood tumors. Together with population-based pediatric cancer registries, this will help decipher pediatric RT needs and deficits. Additionally, the underutilization of palliative RT calls for multidisciplinary palliative care provision for pediatric cancer patients.

Urinary schistosomiasis and the associated bladder cancer: update.

BACKGROUND: Urinary schistosomiasis and its severe complications, mainly bladder cancer, are scarce in non-endemic areas. The deficiency in knowledge and clinical experience of schistosomiasis may lead to inadequate management. Highlighting these topics may be of value, especially with the increased immigration from endemic low-/middle-income countries (LMIC) to non-endemic high-income countries (HIC). Schistosomiasis is a parasitic infection endemic in many low- and middle-income countries. It can affect various systems but is best known for its effect on the urinary system. MAIN BODY: PubMed, Scopus, Google Scholar, and the Cochrane Library databases were searched for urinary schistosomiasis and its related bladder cancer published from 1980 till 2020. Schistosoma haematobium (SH) infecting the urinary bladder was considered by the IARC as group 1 definitive biological carcinogenic agent. Several carcinogenic pathways have been postulated but the exact mechanism(s) are not defined yet. A more thorough understanding of the parasite life cycle was explored to help eradicate the infection especially for the immigrants from endemic areas. This may prevent or slow down the process of carcinogenesis that leads to Schistosoma-associated bladder cancer (SA-BC), which is usually, but not conclusively, squamous cell carcinoma. Treatment of SA-BC generally follows the same guidelines as urothelial Schistosoma-non-associated bladder cancer (SNA-BC) management; however, prospective trials to confirm and refine the treatment approach for SA-BC have been relatively limited. CONCLUSION: The available data showed that despite some etiologic and carcinogenic differences, the oncologic outcomes are generally comparable for SA-BC and NSA-BC when adjusting for stage, risk status, and comorbidities.

Pediatric low grade focal brainstem glioma: outcomes of different treatment strategies and prognostic factors.

Background: This study explores the prognostic factors and outcomes of different treatment modalities in focal brain stem glioma (FBSG). Materials & methods: Pediatric FBSG patients diagnosed during 2010-2017 were retrospectively reviewed for clinical and therapeutic data. Results: A total of 71 cases were identified and the median age was 6.4 years. The 5-year overall- and progression-free survival were 74.5 and 70.6%, respectively. Radiotherapy was the main line of treatment (66.2%) and there were no survival differences between radiotherapy, chemotherapy and surveillance groups. Two independent poor prognostic factors were identified on multivariate analysis: age <8 years and cervicomedullary tumor site (p = 0.02 for both). Conclusion: Surveillance, radiotherapy and chemotherapy have comparable clinical outcomes in pediatric FBSG.

Is economic status the main determinant of radiation therapy availability? The Arab world as an example of developing countries.

BACKGROUND AND PURPOSE: Arab countries share a common location, history, language and culture with different economic characteristics. In this study, we analyze the availability and factors influencing radiotherapy services and cancer mortality incidence ratio (MIR) in Arabic countries. MATERIALS AND METHODS: Data were collected from GLOBOCAN report, World Health Organization, World Bank, United Nation and Directory of Radiotherapy Centre databases. RESULTS: The average number of megavoltage machines (MVM) in Arab countries is 0.84 machine per 1000 cancer patients. The number of MVM per 1000 cancer patients was found to be significantly correlated with gross domestic product (GDP) per capita (r = 0.583, P = 0.006). In addition, it was found to be significantly more in politically stable countries compared to unstable ones (P = 0.004) and more in high and upper-middle income countries (median 0.94 ±â€¯1.0) compared to lower-middle and low income countries (median 0.3 ±â€¯0.51) (P = 0.013). MIR was found to be significantly correlated with GDP per capita, physicians per 1000 population, MVM per 1000 cancer patients and absolute MVM deficit (r = -0.555, -0.625, -0.42, -0.436 and P = 0.009, 0.006, 0.047, 0.043, respectively). On multivariate regression analysis, the number of physicians per 1000 population had the strongest prediction of MIR in Arabic countries (P = 0.01). CONCLUSION: Although the economic status is of paramount importance, it is not the only factor determining the quantity and quality of radiotherapy services in the Arab world. More efforts are urgently needed to improve the status of radiation oncology and fill its gap in the Arab countries.

Radiation Therapy Availability in Africa and Latin America: Two Models of Low and Middle Income Countries.

Access to radiation facilities in low- and middle-income countries (LMIC) is far from optimal. Latin America and Africa represent 55% of LMIC, and radiation therapy facilities are available in only 70% and 46% of the countries, respectively. Only 3 countries in both regions meet the International Atomic Energy Agency's recommendation of 250,000 population per megavoltage machine (MVM). In Africa, the mean population served by 1 MVM is 3.56 million, compared with 0.65 million in Latin America. The distribution of radiation facilities in both regions varies according to income group. In Latin America, lower-middle-income countries have a distribution of 1.64 million inhabitants per MVM, as opposed to 0.64 and 0.49 million inhabitants per MVM in upper-middle- and high-income countries, respectively. In Africa, a distribution of 39.8, 2.47, and 0.8 million people per MVM is present in low-, lower-middle-, and upper-middle-income countries, respectively. Significant correlations were clearly demonstrated between population per MVM and gross domestic product (GDP) per capita (r = -0.3, P = .014), percentage of current health expenditure from GDP (r = -0.4, P = .014), life expectancy (r = -0.5, P = .0007), and cancer mortality incidence ratio (r = 0.4, P = .003). Stepwise multivariate regression showed that life expectancy was the only statistically significant factor (P = .001). These findings may indicate the detrimental impact of low radiation therapy coverage on life expectancy and cancer mortality incidence ratio in LMIC. It is noteworthy that in Latin America, a significant negative correlation was noted between population per MVM and GDP per capita (r = -0.6, P = .0004), as opposed to Africa (r = -0.4, P = .075). This indicates that African countries face challenges other than income level in addressing radiation therapy needs. More international efforts are urgently required to address the crisis of unmet radiation therapy needs in LMIC.

Induction of apoptosis by pyrazolo[3,4-d]pyridazine derivative in lung cancer cells via disruption of Bcl-2/Bax expression balance.

In the rapidly expanding era of cancer target therapy, regulators of apoptosis are emerging as attractive therapeutic targets. X-linked inhibitor of apoptosis (XIAP) is of specific interest owing to its characteristic overexpression in a wide variety of neoplasms, with a resultant survival advantage for tumor cells and treatment resistance. In this study, we examined three pyrazolo [3,4-d] pyridazine derivatives (PPDs) through molecular modeling and studied their modes of interaction with XIAP-BIR3 domain. PPD-1, which possessed the highest binding affinity with XIAP, was tested on A549 (lung cancer cell line); HCT-116 (colorectal carcinoma cell line); HEPG2 (liver carcinoma cell line), HFB4 (normal human skin melanocyte cell line) and WI-38 (human embryonic lung fibroblasts). In comparison to cisplatin as a positive control, PPD-1 yielded remarkable cytotoxicity on all cancer cell lines, with the highest anti-tumor activity on A549 and a favorable therapeutic ratio. Flow cytometry studies concluded that PPD-1 treatment induces Sub G1 and G2/M cell cycle arrest and apoptosis. The percentage of apoptotic cells in PPD-1 treated A549 cells was considerably higher than that in untreated cells (10.06% vs 0.57%, respectively). To further investigate the mechanism of induction of apoptosis by PPD-1, Real time-PCR was used to quantify the expression levels of key apoptotic regulators. Significant overexpression of the effector capsase-3, pro-apoptotic bax and tumor suppressor gene p53 were noted as compared to untreated cells (7.19 folds, 7.28 folds, and 5.08 folds, respectively). Moreover, PPD-1 inhibited the expression of the anti-apoptotic bcl-2 gene to 0.22 folds. These findings demonstrate that PPD-1 treatment disrupts the Bcl-2/BAX balance in lung cancer cell lines, leading to apoptosis induction possibly through intrinsic mitochondria-dependent pathway. These novel insights elucidate the mechanism of PPD-1 cytotoxicity in lung cancer cell lines and offer a promising therapeutic approach that needs further study.

Inhibitors of apoptosis: clinical implications in cancer.

Inhibitor of apoptosis (IAP) family comprises a group of endogenous proteins that function as main regulators of caspase activity and cell death. They are considered the main culprits in evasion of apoptosis, which is a fundamental hallmark of carcinogenesis. Overexpression of IAP proteins has been documented in various solid and hematological malignancies, rendering them resistant to standard chemotherapeutics and radiation therapy and conferring poor prognosis. This observation has urged their exploitation as therapeutic targets in cancer with promising pre-clinical outcomes. This review describes the structural and functional features of IAP proteins to elucidate the mechanism of their anti-apoptotic activity. We also provide an update on patterns of IAP expression in different tumors, their impact on treatment response and prognosis, as well as the emerging investigational drugs targeting them. This aims at shedding the light on the advances in IAP targeting achieved to date, and encourage further development of clinically applicable therapeutic approaches.