MEK inhibitors in cancer treatment: structural insights, regulation, recent advances and future perspectives.

MEK1/2 are critical components of the RAS-RAF-MEK-ERK or MAPK signalling pathway that regulates a variety of cellular functions including proliferation, survival, and differentiation. In 1997, a lung cancer cell line was first found to have a MEK mutation (encoding MEK2P298L). MEK is involved in various human cancers such as non-small cell lung cancer (NSCLC), spurious melanoma, and pancreatic, colorectal, basal, breast, and liver cancer. To date, 4 MEK inhibitors i.e., trametinib, cobimetinib, selumetinib, and binimetinib have been approved by the FDA and several are under clinical trials. In this review, we have highlighted structural insights into the MEK1/2 proteins, such as the αC-helix, catalytic loop, P-loop, F-helix, hydrophobic pocket, and DFG motif. We have also discussed current issues with all FDA-approved MEK inhibitors or drugs under clinical trials and combination therapies to improve the efficacy of clinical drugs. Finally, this study addressed recent developments on synthetic MEK inhibitors (from their discovery in 1997 to 2022), their unique properties, and their relevance to MEK mutant inhibition.

Design, one-pot synthesis, computational and biological evaluation of diaryl benzimidazole derivatives as MEK inhibitors.

MEK mutations are more common in various human malignancies, such as pancreatic cancer (70-90%), mock melanoma (50%), liver cancer (20-40%), colorectal cancer (25-35%), melanoma (15-20%), non-small cell lung cancer (10-20%) and basal breast cancer (1-5%). Considering the significance of MEK mutations in diverse cancer types, the rational design of the proposed compounds relies on the structural resemblance to FDA-approved MEK inhibitors like selumetinib and binimetinib. The compound under design features distinct substitutions at the benzimidazole moiety, specifically at positions 2 and 3, akin to the FDA-approved drugs, albeit differing in positions 5 and 6. Subsequent structural refinement was guided by key elements including the DFG motif, hydrophobic pocket and catalytic loop of the MEK protein. A set of 15 diverse diaryl benzimidazole derivatives (S1-S15) were synthesized via a one-pot approach and characterized through spectroscopic techniques, including MASS, IR, 1H NMR and 13C NMR. In vitro anticancer activities of all the synthesized compounds were evaluated against four cancer cell lines, A375, HT -29, A431 and HFF, along with the standard drug trametinib. Molecular docking was performed for all synthesized compounds (S1-15), followed by 950 ns molecular dynamics simulation studies for the promising compounds S1, S5 and S15. The stability of these complexes was assessed by calculating the root-mean-square deviation, solvent accessible surface area and gyration radius relative to their parent structures. Additionally, free energy of binding calculations were performed. Based on the biological and computational results, S15 was the most potent compound and S1 and S5 are comparable to the standard drug trametinib.Communicated by Ramaswamy H. Sarma.

Pancreatic Resection for Pancreatic Tumors our Experience at Suburban Hospital.

Introduction: Resection of pancreatic tissue is necessary for many pancreatic diseases. The most common form of cancer, pancreatic duct adenocarcinoma, manifests with early metastases and is thought to be resistant to other currently known treatment regimens. Such tumors present a complex and difficult management and handling challenge for a surgeon. Surgical resection affords a better prognosis with a median survival of 14-20 months following resection and up to 25% 5-year survival rates. In this study, data from 75 pancreatic resections for diverse malignant pancreatic lesions will be presented. Methods: At a teaching institute in Central India, this ongoing longitudinal study began in 2009 and was carried on till 2018. Only 75 of the 122 patients who underwent pancreatic resection were deemed appropriate for the current study. All patients were thoroughly examined after being admitted before being given the option of surgery. There were 22 female patients and 53 male patients. The age range for the group was 34-67 years. Results from a range of different malignancies and various pancreatic resection procedures are presented in this study. Results: One of the most aggressive cancers, pancreatic adenocarcinoma, responds to surgical treatment better than other alternative techniques. Out of 75 patients in our series, 32 had pancreatic head cancer, 28 had periampullary cancer, 2 had duodenal cancer, 8 had distal cholangiocarcinoma, and 1 had mucin-producing cystadenocarcinoma. Four patients had pancreatic cancer in both the body and tail. Fifty-three men and 22 women, ages 34-67 years, Whipple's operation and distal pancreatectomy were the most frequent procedures. In our series, survival ranged from 18 to 24 months, and the 5-year survival rate was 12%, which is primarily seen with periampullary carcinoma. Conclusion: The sole option for long-term survival or a cure for pancreatic cancer is surgery. Chemoradiation is ineffective as a first line of treatment. However, some reports contend that palliative chemotherapy actually improves the quality of life. The biology of the illness rules and determines the result; the kind of surgery performed had no bearing on survival, morbidity, or fatality. Context: The above study was taken up in the context of - pancreatic tumors and pathological types, how imaging helps in deciding the plan of surgical management without biopsy. Outcomes of pancreatic resections for pancreatic cancer. Settings and Design: In a suburban hospital which is a tertiary care center, this longitudinal prospective study was conducted from 2009 to 2018.

Résumé Introduction: La résection du tissu pancréatique est nécessaire pour de nombreuses maladies pancréatiques. La forme de cancer la plus courante, l'adénocarcinome du canal pancréatique, se manifeste par des métastases précoces et on pense qu'elle est résistante aux autres schémas thérapeutiques actuellement connus. De telles tumeurs présentent un défi de gestion et de manipulation complexe et difficile pour un chirurgien. La résection chirurgicale offre un meilleur pronostic avec une survie médiane de 14 à 20 mois après la résection et jusqu'à 25 % de taux de survie à 5 ans. Dans cette étude, les données de 75 résections pancréatiques pour diverses lésions pancréatiques malignes seront présentées. Méthodes: Dans un institut d'enseignement du centre de l'Inde, cette étude longitudinale en cours a débuté en 2009 et s'est poursuivie jusqu'en 2018. Seuls 75 des 122 patients ayant subi une résection pancréatique ont été jugés appropriés pour l'étude actuelle. Tous les patients ont été soigneusement examinés après leur admission avant de pouvoir subir une intervention chirurgicale. Il y avait 22 patients de sexe féminin et 53 patients de sexe masculin. La tranche d'âge du groupe était de 34 à 67 ans. Les résultats d'une gamme de différentes tumeurs malignes et de diverses procédures de résection pancréatique sont présentés dans cette étude. Résultats: L'un des cancers les plus agressifs, l'adénocarcinome du pancréas, répond mieux au traitement chirurgical que les autres techniques alternatives. Sur les 75 patients de notre série, 32 avaient un cancer de la tête du pancréas, 28 un cancer périampullaire, un cancer duodénal, 8 un cholangiocarcinome distal et 1 un cystadénocarcinome producteur de mucine. Quatre patients présentaient un cancer du pancréas au niveau du corps et de la queue. Cinquante-trois hommes et 22 femmes, âgés de 34 à 67 ans, l'opération de Whipple et la pancréatectomie distale étaient les procédures les plus fréquentes. Dans notre série, la survie variait de 18 à 24 mois et le taux de survie à 5 ans était de 12 %, ce qui est principalement observé dans le carcinome périampullaire. Conclusion: La seule option pour survivre à long terme ou guérir le cancer du pancréas est la chirurgie. La chimioradiothérapie est inefficace en première intention. Cependant, certains rapports affirment que la chimiothérapie palliative améliore réellement la qualité de vie. La biologie de la maladie gouverne et détermine le résultat ; le type d'intervention chirurgicale pratiquée n'avait aucune incidence sur la survie, la morbidité ou le décès. Contexte: L'étude ci-dessus a été reprise dans le contexte des tumeurs pancréatiques et des types pathologiques, comment l'imagerie aide à décider du plan de prise en charge chirurgicale sans biopsie. Résultats des résections pancréatiques pour le cancer du pancréas. Paramètres et conception: Dans un hôpital de banlieue qui est un centre de soins tertiaires, cette étude prospective longitudinale a été menée de 2009 à 2018. Mots-clés: Complications, résections pancréatiques, résultats.

Multi-responsive albumin-lonidamine conjugated hybridized gold nanoparticle as a combined photothermal-chemotherapy for synergistic tumor ablation.

Herein, we developed a multifunctional nanoplatform based on the nanoassembly of gold nanoparticles (GNP) conjugated with lonidamine (LND) and aptamer AS1411 (AS-LAGN) as an effective cancer treatment. Conjugating AS1411 aptamer on the surface of the nanoparticle significantly improved particle accumulation in cancer cells via specific affinity toward the nucleolin receptors. In vitro study clearly revealed that laser irradiation-based hyperthermia effect enhanced the chemotherapeutic effects of LND. Combinational treatment modalities revealed significant apoptosis with higher cell killing effect due to increased ROS production and inhibition of cell migration. GNP's ability to convert the excited state photon energy into thermal heat enabled synergistic photothermal/chemotherapy with improved therapeutic efficacy in animal models. Moreover, immunohistochemistry staining assays confirmed the ability of AS-LAGN to induce cellular apoptosis/necrosis and ablation in tumor tissues, without causing evident damages to the surrounding healthy tissues. Altogether, this AS-LAGN nanoplatform could be a promising strategy for mitochondria-based cancer treatment. STATEMENT OF SIGNIFICANCE: We have designed a facile biodegradable multifunctional nanocarrier system to target the mitochondria, the major "power house" of the cancer cells. We have constructed a multifunctional nanoassembly of protein coronated gold nanoparticles (GNP) conjugated with lonidamine (LND) and aptamer AS1411 (AS-LAGN) as an effective combination of phototherapy with chemotherapy for cancer treatment. The LND was conjugated with albumin which was in turn conjugated to GNP via redox-liable disulfide linkage to generate oxidative stress and ROS to kill cancer cells. GNP's ability to convert the excited state photon energy into thermal heat enabled synergistic photothermal/chemotherapy with improved therapeutic efficacy in animal models. Consistently, AS-LAGN showed enhanced antitumor efficacy in xenograft tumor model with remarkable tumor regression property.

Involvement of non-governmental organisations in the RNTCP.

To get the maximum benefit from Revised National TB Control Programme (RNTCP) developing partnership with private health providers outside government health system is very important. RNTCP actively seeks the participation of the NGOs by sensitising them with DOTS strategy. A broad framework for involvement of NGOs has been evolved by RNTCP Schemes for NGOs and RNTCP collaboration are elaborated. Over 514 NGOs are currently participating in the programme under one or another scheme. In addition to the guidelines developed by Government of India, innovative forms of partnership between RNTCP, NGOs and other private health providers should be encouraged.