Recent advances in microbial toxin-related strategies to combat cancer
Graphical abstract
Introduction
Toxins are the proteins or secondary metabolites, produced by the prokaryotic or eukaryotic organisms that are poisonous in nature and are responsible for several infections or diseases that cannot be cured by antibiotics or chemotherapeutic agents [1]. Microbial toxins are produced from various microorganisms including bacteria, fungi, algae, protozoa, etc. Several functions are performed by microbial toxins in different environments including competition for nutrients by antimicrobial agents or to inhibit particular environmental niches. Additionally, they act as virulence factors involved with the undisputed offensive role of causing infection and diseases through evading mechanisms of immune cells response, required for clearing up the pathogenic challenges [2,3]. Historically, the importance of microorganisms as anticancer agents has been observed almost 150 years ago when accidental erysipelas (Streptococcus pyogenes) infections improved the condition of hospitalized patients with cancer [4]. Further, in the latecentury regression of tumors was observed in patients who acquired skin infection due to Streptococcal bacteria. This led to the innovation of cancer immunotherapy and subsequently formulation of a vaccine using killed bacterial species (Coley's toxins) [5,6] successful to prolong the regression of many advanced malignancies and to treat myelomas, carcinomas, lymphomas, melanomas and sarcomas [7]. The development of ‘Coley's toxins’ gave way to the promising field of microbial toxin-based cancer therapy.
Cancer remains a worldwide health concern and in developed countries, it is regarded as the second foremost reason for death [[186], [187], [188]]. Among different cancers, breast cancer is considered to have the greatest effect on the global patient health care system. Every year, tens of millions of the population are diagnosed with various forms of cancer and more than half ultimately die due to cancer growth [8]. Recurrence, uncontrolled cell division, resistance to apoptosis, dysfunctioning of immune surveillance and metastasis has always been among the major causes of death, even with all the current technological developments. The distant metastasis in patients results in high mortality rates and considered to be the major target for successful clinical treatment [[9], [10], [11], [12]]. Apoptosis is dysregulated in cancer, making it easier for cancer cells to survive, leading to cancer growth. Many cancer medicines generate mutations in cancer regulating genes, which should kill the cancer cell but instead result in chemoresistance. According to WHO, cancer is the largest cause of death in the world, with approximately 10 million fatalities expected by 2020. In terms of new cancer cases in 2020, the most common were breast (2.26 million cases), lung (2.21 million cases), colon and rectum (1.93 million cases), prostate (1.41 million cases), skin (non-melanoma) (1.20 million cases); and stomach (1.09 million cases). In 2020, the most common causes of cancer death were lung (1.80 million deaths), colon and rectum (935 000 deaths), liver (830 000 deaths), stomach (769 000 deaths) and breast (685 000 deaths) [13,14].
Several therapies such as radiotherapy, surgical therapy, cytotoxic chemotherapy, oncolytic virotherapy, hormonal replacement therapy and immunotherapy are currently used for cancer treatment are associated with several side effects as depicted in Fig.1. Among different chemotherapeutic options, the use of toxins with recent advancement becomes the choice of therapy against cancer cells with improved efficacy of current therapies and benefit of minimized side effects [15]. Cancer immunotherapy combined with effective functionalized nanosystems has emerged as a promising treatment method and its use is fast increasing. The importance of stimuli-responsive nanosystems and nanomedicine-based cancer immunotherapy, a subfield of immunology cannot be overstated. The advancement of cancer nanomedicine has propelled immunotherapy’s results to the next level in the contemporary era of medical research. Moreover, future development by targeting the immune system can be a promising anticancer therapy along with an effective targeted response [16]. The existing anticancer therapies have been proved to be highly effective in the inhibition of cancer cell growth, but there are challenges like lack of targeted effects and association of unwanted adverse effects [[17], [18], [19], [20], [21], [22], [23], [24], [25], [26]]. Due to these limitations associated with current anticancer therapies, there is an urgent need for the discovery of novel and innovative anticancer therapies (Fig. 2).
Microbial toxins isolated from different microbial sources such as bacteria, fungus and algae are the promising strategies used to transmit foreign toxic molecules directly to targeted tumor cells. The cellular and molecular mechanisms of immune cells can be eluded by microbial toxins that are the key contagious subunits of various infective microorganisms. To clear up the pathogen challenge, microbial toxins can contribute to depreciated cellular immune responses. The microbial toxins prevailing in food mediums can be broadly classified into three types: (1) Bacterial toxins (2) Fungal toxins (3) Algal toxins. Therefore, in recent years, findings have been focused on the development of the anticancer effect for toxins as one of the promising strategies using which foreign toxic molecules can specifically target tumor cells. Microbial toxin therapy showed great promise for improved anticancer activity [[27], [28], [29], [30], [31]]. Various types of microbial toxins are presented in Fig.3. In this review, we have explored recent advancements of important microbial toxins and their metabolites as other alternative therapy to the existing therapies for the treatment and management of cancer constantly with minimized side effects.
Section snippets
Bacterial toxins as anticancer agents
Bacterial toxins are toxic potent compounds produced and released by a wide range of bacterial pathogens to target host cells. These toxins are identified as soluble substances that can change the usual metabolism of host cells with harmful effects. Generally, it is possible to split bacterial toxins into several classes, based on their character and mechanism of action. However, they are divided into two broad categories as exotoxins or endotoxins, summarized in Fig.4 [[32], [33], [34], [35]].
Fungal toxins as anticancer agents
Fungal toxins are found to be highly toxic secondary metabolic products obtained from various moulds, some of them related to genera Fusarium, Aspergillus and Penicillium. As per estimation more than 300 of the fungal metabolites are reported to be harmful to animals and humans beings. The important fungal toxin produced by some species is aflatoxins, citrinin, patulin, ochratoxin-A, trichothecene, nivalenol, deoxynivalenol (Table 2), excessively affecting economic agricultural benefits, food
Algal toxins as anticancer agents
Marine algae are unicellular plants that influence the global carbon and water cycle. The demand for microalgae and macroalgae as nutraceuticals and nutritional supplements is growing day by day as lipids, pigments, omega-3 fatty acids, carotenoids, vitamins, polysaccharides and other fine chemicals are tremendous sources of these foods. Some marine algae are also testified for their anticancer activity. Third of the most sold drugs and their derivatives are from natural origin and as Dyshlovoy
Challenges and alternative approaches
Currently, very few microbial toxins have been explored for cancer therapy, since most of these toxins have been used to study or affect specific signaling pathways in mammalian cells since they have well-known structures, cellular receptors, molecular mechanisms and uptake pathways [39]. Several formats of microbial toxins have been granted patents (Table 4) and several others are undergoing clinical trials to assess the effectiveness of microbial toxin therapy in humans [162]. Few custom-made
Conclusions
The application of toxins to combat cancer cells has evolved constantly with minimized side effects. This review deals with the recent advancements of important microbial toxins in this field. This therapy is getting popularized as a very promising therapy. These microbial toxins have diverse mechanisms of action, for example, bacterial toxins act by inhibiting protein synthesis, reducing cell growth and proliferation which leads to cell death through apoptotic activity. Fungal toxins cause
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgement
The authors’ PCS, VKT and MB would like to express their sincere thanks to Newton Bhabha Fundfor providing the foundation to establish this cross-country interdisciplinary research collaboration through the Researcher Links scheme. One of the authors (Ms Diksha Sharma) is thankful to the Department of Science and Technology, Government of India, New Delhi for financial assistance under the DST INSPIRE fellowship programme.
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