The Ways Of Treatment Of Cancer

Several classes of chemotherapeutic agents along with radiation and other therapies have been evolved over period of time. Still cytotoxicity and drug resistance remains the major hurdle for the treatment of cancer. Antitumour agents that can modulate apoptosis is highly sought after recently for the management and treatment of cancer. The present studies demonstrated that chrysin isolated from Alpinia galanga exhibited differential sensitivity towards cancer cells tested with low IC50 values without exerting significant toxicity to normal cells. structure activity Studies suggest that the chemical structure of 5,7-dihydroxyflavone is highly favourable for inducing cytotoxicity in cancer cells. Chrysin is reported to induce cell growth arrest, apoptosis, and ER stress and inhibits the activation of STAT3 through the generation of reactive oxygen species in bladder cancer cells (Yi et al. 2018). Moreover structural modifications of chrysin and synergistic interactions with other drugs or flavonoids also could be tried and might render more potent than administration of unmodified chrysin (Boon et al. 2010). It is also reported that acacetin (5,7-dihydroxy-4'-methoxyflavone) exhibits in vitro and in vivo anticancer activity through the suppression of NF-κB/Aktsignaling in prostate cancer cells (Kim et al. 2014).

A very unique feature of cancer cells is its evasion from apoptosis due to metabolic abnormalities or genetic mutations; hence an anti-cancer agent should possess the ability to induce apoptosis in cancer cells (Ralph et al. 2008). The effectiveness of chrysin lies in the fact that it is selectively toxic against the DLA and lung cancer cell lines tested, sparing the normal fibroblast cells and lymphocytes. Annexin-V FITC experiments suggest that the cell membrane being intact, the cells are impermeable to propidium iodide during the early stages of apoptosis whereas during the later stages of apoptosis, the cells become permeable to both the dyes. The necrotic cells are permeable only to PI and not to annexin for there is no phosphadidyl serine translocated to the extracellular leaflet of the membrane to which annexin binds. The flow cytometric data revealed that most of the compound treated cells took up both the dyes in a dose and time dependent fashion revealing the induction of late stages of apoptosis by these compounds on the lymphoma and lung cancer cells. The studies on induction of apoptosis revealed chrysin could induce caspase-3 expression and apoptosis in cancer cells. Caspases are central initiators and executioners of apoptosis and active caspase-3 is a marker for cells undergoing apoptosis and it cleaves and activates other caspases as well as relevant targets like PARP and Bcl-2 (David et al. 2013).

Liver being a de-toxification organ is always susceptible to injury from drugs and other chemicals. Serum enzyme assays are very sensitive and serve as useful markers for tissue damage caused by toxicity of chemicals. Also, kidney function tests to estimate urea and creatinine clearance tests measure glomerular filtration and used to assess renal function. The positive control used was cyclophosphamide and a dosage of 25mg/kg bw was fixed based on the previous reports which stated that the established maximum tolerated dose (MTD) for single dose was 300 mg/kg bw (Wayne et al. 2017). Here we employed different lower doses cumulatively that came upto approximately 300 mg/kg bw throughout the 14 days experimentation. Gross histopathological tissue examinations and blood tests from mice confirmed that chrysin did not cause tissue damage except at very high doses. The studies confirmed that chrysin induced antitumour activity at dose of 1.3 mg/kg bw. The results of mean survival time, increase in life span and tumour regression was found to be very supportive towards this. Most importantly the active doses were relatively non-toxic to mice at this dose. Moreover, the ascites tumor model used in the present study resembles a solid tumor model, with angiogenesis and generation of a connective tissue stroma. The DLA cells were selected because during the late tumour bearing stages, DLA growth has been shown to be associated with inhibition of humoral and cell mediated immune responses involving the abrogated functions of macrophages, B and T cells (Muthu et al.2010; Kumari et al. 2017). In this study, chrysin has been proven to delay tumor progression induced by DLA cells and the cytotoxic effects that inhibit growth of tumor cells, may be due to their potent activation of the caspase enzyme, as demonstrated in the in vitro part.

Treatment of cancer with chemotherapy and radiation therapy has severe toxic side effects that damage healthy proliferating cells, such as hematopoietic precursors, hair follicle cells, and the epithelial lining of the intestine. These side effects often limit the doses of chemotherapy administered and allow tumor cells to escape treatment and to develop drug resistance (Xiaomei et al. 2000). Administrating high doses of cytotoxic drugs cannot be limitlessly increased and so combination therapy evolved and was expected to achieve high therapeutic efficacy at lower drug dose in synergistic combinations (Karen et al. 2008). Moreover, combining multiple cytotoxic drugs for cancer therapy might simultaneously lead to a potential danger of drug interaction toxicity and cross-resistance (Mihaela et al. 2014). Therefore, it is urgent to develop a novel combination therapy strategy for cancer treatment. The combination treatment using cyclophosphamide along with chrysin showed better outcome in the blood, liver and kidney function tests indicating protection to the vital organs. The combination treatment efficiently decreased the tumour volume and increased the life span of tumour bearing animals compared to cyclophosphamide treated group. The possibility of reduction in concentration of cyclophosphamide, due to the synergistic effects with chrysin can reduce toxicity and off-target interactions, providing a mechanism to improve the treatment strategy.

The hope for a successful resolution in the design of anti-cancer agents lies in diverting the cells to the engagement of apoptosis. This study presents a comparatively and comprehensive exploration on potency of chrysin alone and in synergistic combination with a clinically used drug for cancer. This novel combination could generate synergistic effects on cancer treatments, which has to be taken up in the future as it is highly promising to enhance therapeutic efficacy.