A review on metal complexes and its anti-cancer activities: Recent updates from in vivo studies.

Research into cancer therapeutics has uncovered various potential medications based on metal-containing scaffolds after the discovery and clinical applications of cisplatin as an anti-cancer agent. This has resulted in many metallodrugs that can be put into medical applications. These metallodrugs have a wider variety of functions and mechanisms of action than pure organic molecules. Although platinum-based medicines are very efficient anti-cancer agents, they are often accompanied by significant side effects and toxicity and are limited by resistance. Some of the most studied and developed alternatives to platinum-based anti-cancer medications include metallodrugs based on ruthenium, gold, copper, iridium, and osmium, which showed effectiveness against many cancer cell lines. These metal-based medicines represent an exciting new category of potential cancer treatments and sparked a renewed interest in the search for effective anti-cancer therapies. Despite the widespread development of metal complexes touted as powerful and promising in vitro anti-cancer therapeutics, only a small percentage of these compounds have shown their worth in vivo models. Metallodrugs, which are more effective and less toxic than platinum-based drugs and can treat drug-resistant cancer cells, are the focus of this review. Here, we highlighted some of the most recently developed Pt, Ru, Au, Cu, Ir, and Os complexes that have shown significant in vivo antitumor properties between 2017 and 2023.

Immunotherapeutic potential of ethanolic olive leaves extract (EOLE) and IL-28B combination therapy in ENU induced animal model of leukemia.

Cytokine therapies have shown promising results against cancers. Cytokines are secreted naturally from different bodily cells. These have fewer side effects but higher specificity than chemotherapy and radiation therapy. In leukemia, changes in normal hematopoiesis and defective leukocyte production limit the efficacy of immunotherapy by reducing the count of functional immune cells. Therefore, the treatment of leukemia needs advanced therapeutics that can target multiple cancer sustaining mechanisms. In combination therapy, using two different therapeutic agents affect cancer growth in many ways and sometimes gives synergistic effects. Here, we examined the effect of the ethanolic olive leaf extract (EOLE) and IL-28B in combination. N-N' Ethyl-nitrosourea (ENU) induced leukemia in Swiss albino mice was treated with EOLE for four weeks and IL-28B for one week after confirming the development of leukemia. The combination of EOLE and IL-28B significantly reduced the blast cell and total WBC counts in the peripheral blood, altered the levels of various cytokines in plasma, and induced the functional activity of NK cells in leukemic mice. The induced NK activity correlates with increased expression of perforin and granzyme studied at the gene level through real-time (RT)-PCR. The treatment of leukemic mice with combined EOLE and IL-28B has also caused an increased serum IL-10 and IFN-γ level, and reduced serum TGF-ß indicates improved overall immunity. Altogether, the combination of EOLE and IL-28B has given substantial therapeutic activity against leukemia.

A review of the mutagenic potential of N-ethyl-N-nitrosourea (ENU) to induce hematological malignancies.

This review is intended to summarize the existing literature on the mutagenicity of N-ethyl-N-nitrosourea (ENU) in inducing hematological malignancies, including acute myeloid leukemia (AML) in mice. Blood or hematological malignancies are the most common malignant disorders seen in people of all age groups. Driven by a number of genetic alterations, leukemia rule out the normal proliferation and differentiation of hematopoietic stem cells (HSCs) and their progenitors in the bone marrow (BM) and severely affects blood functions. Out of all hematological malignancies, AML is the most aggressive type, with a high incidence and mortality rate. AML is found as either de novo or secondary therapeutic AML (t-AML). t-AML is a serious adverse consequence of alkylator chemotherapy to the cancer patient and alone constitutes about 10%-20% of all reported AML cases. Cancer patients who received alkylator chemotherapy are at an elevated risk of developing t-AML. ENU has a long history of use as a potent carcinogen that induces blood malignancies in mice and rats that are pathologically similar to human AML and t-AML. ENU, once entered into the body, circulates all over the body tissues and reaches BM. It creates an overall state of suppression within the BM by damaging the marrow cells, alkylating the DNA, and forming DNA adducts within the early and late hematopoietic stem and progenitor cells. The BM holds a weak DNA repair mechanism due to low alkyltransferase, and poly [ADP-ribose] polymerase (PARP) enzyme content often fails to obliterate those adducts, acting as a catalyst to bring genetic abnormalities, including point gene mutations as well as chromosomal alterations, for example, translocation and inversion. Taking advantage of ENU-induced immune-suppressed state and weak immune surveillance, these mutations remain viable and slowly give rise to transformed HSCs. This review also highlights the carcinogenic nature of ENU and the complex relation between the ENU's overall toxicity in the induction of hematological malignancies.

Olive leaves extract alleviates inflammation and modifies the intrinsic apoptotic signal in the leukemic bone marrow.

Introduction: Current anti-leukemic chemotherapies with multiple targets suffer from side effects. Synthetic drugs with huge off-target effects are detrimental to leukemic patients. Therefore, natural plant-based products are being increasingly tested for new anti-leukemic therapy with fewer or no side effects. Herein, we report the effect of ethanolic olive leaves extract (EOLE) on the K562 cell line and on the bone marrow (BM) of N-ethyl-N-nitrosourea (ENU)-induced leukemic mice. Methods: Using standard methodologies, we assessed viability, chromatin condensation, and induction of apoptosis in EOLE-treated K562 cells in-vitro. The anti-leukemic activity of EOLE was assayed by measuring ROS, levels of various cytokines, expression of iNOS and COX-2 gene, and changes in the level of important apoptosis regulatory and cell signaling proteins in-vivo. Result: K562 cells underwent apoptotic induction after exposure to EOLE. In the BM of leukemic mice, EOLE therapy decreased the number of blast cells, ROS generation, and expression of NF-κB and ERK1/2. IL-6, IL-1ß, TNF-α, iNOS, and COX-2 were among the inflammatory molecules that were down-regulated by EOLE therapy. Additionally, it decreased the expression of anti-apoptotic proteins BCL2A1, BCL-xL, and MCL-1 in the BM of leukemic mice. Discussion: Chronic inflammation and anomalous apoptotic mechanism both critically contribute to the malignant transformation of cells. Inflammation in the tumor microenvironment promotes the growth, survival, and migration of cancer cells, accelerating the disease. The current investigation showed that EOLE treatment reduces inflammation and alters the expression of apoptosis regulatory protein in the BM of leukemic mice, which may halt the progression of the disease.

Bromelain and Olea europaea (L.) leaf extract mediated alleviation of benzo(a)pyrene induced lung cancer through Nrf2 and NFκB pathway.

Lung cancer is the most aggressive as well as deadly form of cancer and most of the lung cancer cases are involved in direct smoking or passive smoking. Oxidative stress and pulmonary inflammation regulated by some transcription factors like Nrf2, NF-κB etc. play important roles in lung cancer. Various combinations of therapies are currently attributed to lung cancer treatment. A plethora of evidence supports that the consumption of plant-derived foods can prevent chronic diseases like cancer. Leaves of olive (Olea europaea L.) are rich in phenolic compounds which are having antioxidant and anti-inflammatory property. Also, bromelain from pineapple juice and from pineapple stem is a potent anti-inflammatory agent. We took a pragmatic approach to prevent carcinogenesis by supplementing the combination of these two extracts. In this study, we have tried to evaluate the amelioration of various hallmarks associated with benzo(a)pyrene-induced lung carcinogenesis upon the combinatorial treatment of ethanolic olive leaf extract (EOLE) and bromelain. We have studied the role of EOLE in amelioration of BaP-induced oxidative stress in the lung. As several reports of anticancer activity of bromelain are available, we have combined EOLE with bromelain to study their protective role against BaP-mediated lung damage. Changes in DNA integrity, LPO level in lung after EOLE-treated animal were examined. Then, we have evaluated the synergistic role of EOLE and bromelain. We have found that EOLE in combination with bromelain was able to increase the translocation of Nrf2 from cytoplasm to nucleus and decrease the translocation of NF-κB from cytoplasm to nucleus. Combination of treatment also reduced the expression of TNFα, IL-6, and some matrix metalloproteinases in lung tissue. Our findings suggest that EOLE and bromelain can synergistically reduce the BaP-induced lung carcinogenesis associated with inflammation and oxidative stress via regulating the expression of various inflammatory markers and also modulating the activity of pulmonary antioxidant armories.

Understanding the complicated relationship between antioxidants and carcinogenesis.

Reactive oxygen species (ROS) are generated as by-product of cellular respiration and also due to the exposure of various xenobiotics, whereas mitochondrial electron transport chain is considered as the main source of ROS generation. The sequential addition to molecular oxygen gives rise to various forms of ROS like superoxide anion, peroxide, hydroxyl radical, hydroxyl ion, and so forth. However, the uncontrolled level of ROS generation and accumulation alters the body homeostasis. Excessive generation of ROS leads to oxidative stress and various kinds of diseases including cancer. To counteract ROS, enzymatic and nonenzymatic antioxidants' armory is available in our body. Apart from endogenous antioxidants, we are also consuming various exogenous antioxidants. Antioxidants protect us from ROS-mediated damages and inhibit ROS-induced carcinogenesis. Recent studies have revealed that antioxidants could also act as tumor-promoting agents. Various anticancer drugs are used to kill the cancer cells through the generation of oxidative stress in them, but the cancer cells can counteract the effect with the help of various endogenous as well as exogenous antioxidants. Our review will summarize the multifaceted relationship between antioxidants and carcinogenesis, and it will help to create new directions in antioxidant-based chemotherapy.

Bromelain plus peroxidase reduces non-Hodgkin lymphoma progression in invivo via up-regulation of antioxidant enzymes and modulating apoptotic protein expression.

Aim: Pineapple (Ananas comosus (L.) Merr.) is a good source of bromelain (B) and also contain peroxidase. The objective of this study is isoaltion of bromelain plus peroxidase (BP) from the pineapple fruit to evaluate the anticancer activity of BP from the pineapple fruit of Tripura, compared to commercial bromelain against ascitic Dalton's lymphoma cells (DLA) in mice. Methods: By acetone precipitation BP was isolated from the pineapple. Animals bearing DLA, receive B and BP orally for 15 alternative days. Apoptotic proteins are assayed using western blot. Results: BP treated mice showed recover of hemoglobin and WBC count compared to control lymphoma animal. The animal showed significant reduction of body weight due to reduced tunor load and elevated reactive oxygen species (ROS) production, elevated levels of vitamin C and vitamin E and other antioxidants in blood after BP treatment. Histology of liver and kidney also shows restored architecture in BP treated animal compared to only B treated group. BP treatment upregulates the cytochrome C, BAD, and BAX protein and downregulates the Bcl-2 and NF-kß occuring upon BP treatment in the DLA cells collected from lymphoma animal. This induce the apoptosis of DLA cells in lymphoma animal and reduce the tumor load. Conclusion: The present findings suggest that BP from pineapple improves the survival of the induced lymphoma animal compared to only B which may be used as therapeutic target.