Drug-delivery systems of phytochemicals as therapeutic strategies in cancer therapy

By Akhileshwar Kumar Srivastava, Divya Singh and Rajesh Kumar Singh

Phytochemicals and derivatives have become promising alternatives to increase treatment potential in cancer patients with minimal side effects. Drug-delivery Systems of Phytochemicals as Therapeutic Strategies in Cancer Therapy elucidates the importance of various phytochemicals in cancer therapy and explains various routes/methods to deliver phytochemicals for overcoming the problems associated with delivery system in cancer treatment.

Several nanotechnological methods are followed to enhance drug solubility, sustainability, bioavailability and gastrointestinal permeability of these phytochemicals. The advanced field of drug-delivery systems explains that combination therapy for cancer treatment has important benefits over mono-delivery therapeutics. Natural compounds, because of their biobased origin, have drawn higher attention than synthetic drugs. Synthesis of nano-phytomedicines has impacted the bioavailability of phytochemicals. Novel formulations have been synthesized loaded with phytochemicals and have revealed extraordinary results in treatment of various cancers.

Current understanding of the relevant information presented in Drug-delivery systems of phytochemicals as therapeutic strategies in cancer therapy fulfils the requirements of oncologists, molecular biologists, pharmacologist and related researchers, who want to work in the areas of drug development targeting phytochemicals for cancer therapy

• Explains the significance of phytochemicals in cancer therapy, along with their pharmacologic action
• Elucidates the importance of various phytochemicals in cancer therapy
• Explains the emerging need of drug-delivery system for plant metabolites
• Deciphers the various drug-delivery systems for phytomedicines involved in cancer treatments
• Describes the crucial role of nanotechnology in the development of drug-delivery systems for anticancer phytochemicals
• Explores the challenges associated with developing drug-delivery systems for phytochemicals to cure cancer

• Language: English
• Publisher: Academic Press
• Release date: Nov 7, 2023
• ISBN: 9780443159619

Akhileshwar Kumar Srivastava

Dr. Akhileshwar Kumar Srivastava works as a Research Associate (ICMR) in CSIR-Central Food Technological Research Institute, Mysore, India. In his eight years of research, he has published approximately 20 research articles and book chapters in international and national journals of repute. His research specialization is primarily in the area of pharmacognosy with genetics, metabolomics, bioinformatics, and molecular biology-associated targeting cancer diseases. In addition, he has studied at Augusta University (formerly, Georgia Regents University) in Augusta, GA, United States on a J-1 Exchange Scholar Visa and at Ben-Gurion University, Israel. He is also a life member fellow in Indian Science Congress and Agriculture, Nutrition and Health Academy, United Kingdom.

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Chapter 1: Significance of phytochemicals in cancer therapy

Abstract

Nowadays, cancer has become a serious health problem, which continues to be a leading cause of death over world. Expanding knowledge of the molecular events associated with cancer progression has accompanied to the development of an enormous number of anticancer regimens. In general, the chemopreventive agents impede the development of cancer either by inhibiting DNA damage, which causes malignancy, or by reversing or checking the division of premalignant cells with DNA damage. However, the continuous rise in cancer cases, failure of conventional drugs to curb cancer, and highly toxicity of chemotherapies apparently need alternative approaches. Naturally found compounds from plants referred as phytochemicals serve as critical resources for novel drugs for several diseases including cancer. Some instances such as taxol analogs, vinca alkaloids such as vincristine, vinblastine, and podophyllotoxin analogs are highly prevalent in cancer therapy. Such phytochemicals often act by regulating molecular events causing growth and development of cancer. The certain mechanisms include enhancing antioxidant status, carcinogen suppression, stopping proliferation, stimulation of cell cycle arrest and apoptosis, and regulation of the immune system. The main objective of this chapter is to explain the significance of phytochemicals in cancer therapy along with their pharmacologic action and molecular or particular targets.

Keywords

Autophagy; Cancer; Molecular targets; Nutraceuticals; Phytochemicals

Introduction

The present accomplishment in accessibility of early prognosis, advanced therapy, and survivorship care of malignancy has directed to advancement in the cancer endurance rates in countries having modern health systems. However, cancer is the second main cause of death worldwide, and one in six deaths is because of cancer. The most prevalent cancer-associated death is due to lung, colon and rectum, liver, stomach as well as breast cancer (Mohapatra et al., 2022). The cancer problem continues to increase worldwide exerting not only severe physical and emotional pressure but also economic strains on individuals, families, communities, and the healthcare structures. The crucial cause behind cancer-related death is the inadequacy of appropriate diagnosis and quality therapy. Primary identification of cancer is more possible to respond well to the accessible therapies resulting in a greater chance of survival. In several examples, the main concern of cancer therapy is systemic toxicity, unavoidable therapeutic resistance, and metastatic relapse (Fares et al., 2020). Because of cancer heterogeneity and its mechanistic intricacy, present cancer treatment is inadequate and urges the need for modern and alternate therapeutics. In this esteem, phytochemicals have evolved as potential regimens for the cure of various cancers and are predicated to be capable of anticancer medicines (Choudhari et al., 2020). Certain epidemiological reports explained a reverse relationship between the usage of phytochemicals and cancer incidence rate. Phytochemicals are found in foods such as vegetables, fruits, cereals, and other parts of plants showing anticancer properties on different types of cancer (Morgan et al., 2023).

Despite advancement in modern therapy, cancer is still the main reason of death in both developing and developed countries. Search for secure and highly efficient chemoprevention and therapy approach is a necessity for the enhancement of patient care in the field. Prevention might be highly powerful and less expensive as cancer is mostly a preventable ailment that could be helped to a better extent to lifestyle. Dietary phytochemicals have been employed for the cure of cancer during history because of their safety, less toxicity, and easily availability. Novel phytochemicals not only interrupt abnormal signaling pathways causing cancer but also synergize with chemotherapy and radiotherapy. Hence, the cancer chemoprevention and therapeutic efficiency of natural phytochemicals are immensely drawing attention of biomedical scientists (Lu et al., 2018).

Cancer chemoprevention might be categorized into primary, secondary, and tertiary events. Populations with no evidence for cancer incidence factors, or those apparently at greater risk because of factors such as effective surgical resection or family history, are kept under group of primary measures. Patients with premalignant lesions having incidence of development of an invasive cancer such as ductal carcinoma in situ might be considered under secondary measures. In these cases, typical procedures of chemopreventive procedure will be largely required, but hardly come into play (Dave et al., 2020). People in primary and secondary chemoprevention classes might be suggested or decide on their own to enhance dietary phytochemical consumption or to use over-the-counter products such as nonsteroidal antiinflammatory medicines. Lastly, tertiary levels can be taken for patients with cancer relapses (De Flora & Ferguson, 2005). An exclusive instance of a tertiary chemopreventive measure is the delivery of tamoxifen or its analogs, or aromatase inhibitors, for patients detected with breast malignancy (Ball et al., 2019). About 2500 years back, Hippocrates suggested let food be thy medicine and medicine be thy food. Since primeval periods, it has been recognized that lifestyle and diet have a significant impact on human health and well-being, as well as playing a major role in the prevention of ailment. Inappropriate dietary habits linked with an inactive lifestyle have showed to be contributory reasons of several pathologies, from cardiovascular ailment to cancer (Marino et al., 2023). The discipline referred to as ‘nutraceutical studies’ explores the food compounds or the active constituents found in foods which have positive impacts for well-being and health, such as the prevention and cure of diseases. This word was invented in 1989 and is taken from the combination of the words nutrition and pharmaceutical (DeFelice, 1995). It recognizes a food or part of a food that could be of plant or animal origin, which has an advantageous pharmaceutical action beyond its nutritional worth. Nutraceutics are sometimes confused with food supplements that have not a certain pharmacological impact on health. A reverse relationship between enough fruit and vegetable consumption and cancer risk has been accomplished. Indeed, it has been explained that risk of cancer can be overcome by over 50% if individuals eat as a minimum five servings of fruits and vegetables daily (Surh, 2003). Instead, obesity is usually linked with poor health and chronic ailment, and there are specific foods that can play role as carcinogens and initiate for cancer development.

Secondary metabolites are mainly synthesized in plants to provide defense against external stresses such as UV, fungal contagion, and the production of free radicals. The compounds so synthesized exhibit a noteworthy collection of structural variations. Noticeably, consumption of such phytochemicals affords human beings with protective impact as well (Baena Ruiz & Salinas Hernández, 2016), possibly by decreasing oxidative stress (ROS) and inflammation (Howes & Simmonds, 2014).

Phytochemicals have antioxidant properties, which have a chemopreventive activity by inhibiting DNA damage brought by oxidative stress in carcinoma. In addition, phytochemicals control cellular and molecular mechanisms such as apoptosis, cell proliferation, cell cycle, DNA repair, metastasis, angiogenesis, and activation/inactivation of oncogenes and tumor-suppressor genes (Chikara et al., 2018; Yadav et al., 2020). Various studies explain that phytochemicals synergize with conventional anticancer drugs to efficiently destroy the cancer cells (Ashrafizadeh et al., 2020; Bayet-Robert & Morvan, 2013; Mohapatra et al., 2022). Nevertheless, the effectiveness of phytochemicals is inadequate because of their greater hydrophobicity, low bioavailability, and necessity for high doses.

Scientific reports suggest that phytochemicals have noteworthy anticancer properties. About 50% of approved anticancer medicines derive from natural sources (Murugesan & Venkatajalapathi, 2020). Such phytochemicals have been examined for anticancer potential at both in vitro and in vivo extents. They have complementary and overlapping events to decrease the carcinogenic progression by scavenging free radicals (Lee et al., 2013), reducing survival and proliferation of cancer cells, as well as inhibiting invasiveness and angiogenesis of cancers (Lu et al., 2018). They produce huge and complex array of activities on various molecular targets and signal transduction events such as membrane receptors (Deng et al., 2017), kinases (Dou et al., 2018), downstream tumor-activator or tumor-suppressor proteins (Adams et al., 2010), transcriptional factors (Zhang et al., 2017), microRNAs (miRNAs) (Petric et al., 2015), cyclins, and caspases (Murugesan & Venkatajalapathi, 2020).

The four main groups of clinically employed plant-based anticancer components such as vinca alkaloids, taxane diterpenoids, camptothecin derivatives, and epipodophyllotoxin. Fig. 1.1 represents chemical structure of some phytochemicals, which shows anticancer potential against various cancers. Despite such phytochemical classes, other plant-based anticancer compounds from distinct classes, e.g., combretastatins, homoharringtonine (omacetaxine mepesuccinate, cephalotaxine alkaloid), and ingenol mebutate, are also employed. Different groups of phytochemicals exhibit anticancer properties by targeting molecular mechanism of cancers, which will be elucidated in this chapter.

Figure 1.1  Chemical structure of different phytocompounds showing anticancer properties.

Current challenges in cancer treatment and management

Cancer is an ailment identified by its plasticity and heterogeneity, which grows at genetic, phenotypic, and pathological extent. Cancer heterogeneity, evolution, and its local or systemic environment control disease development and plays a vital role in response or resistance to treatment and its relapse. Improvements in technologies such as next-generation sequencing, omics studies, single-cell methods, and high-resolution imaging have directed to in-depth cancer profiling at resolution and scale, which was tough to get previously (Guren, 2019). Currently, data science has played a crucial function as artificial intelligence to revolutionize data assessment for cancer screening, diagnosis, and treatment conclusions. For instance, computational data science has developed a central part to extract, assess, and create vast cancer patient data, which provides to know and detect the biomarkers to recruit patients for clinical trials and assess treatment responses. Therapeutic inventions in meticulousness drug and immune oncology have also fruitfully introduced various therapeutic modalities into the clinic (Zugazagoitia et al., 2016). Despite all the aforementioned revolutionizing developments in the field of cancer therapy, still there are various drawbacks that limit its clinical implication for complete cancer regression. One of the crucial issues is that maximum cancer treatment fails to thrive in clinical trials that are a greater challenge for generating alternative therapy options. Hence, maximum phytochemicals showing anticancer properties are not succeeded in clinical trials.

Tumor heterogeneity is generated due to the subclonal genetic variation. This intratumoral heterogeneity (ITH) adopts quick tumor development and reveals a major challenge for cancer therapy as it subsidizes to the deadly result of cancer and failure in recent treatments and imparts drug resistance (Greaves, 2015). The beginning of modern technologies such as next-generation sequencing allowed powerful assessment of cancer development and enhanced the awareness of initiation and progression of cancer, intercellular interaction, and immune microenvironment. Instead of these advancements, the knowledge of ITH and generation of resistance subclones in cancer is insufficient, which requires more studies to be considered for developing clinical trials (McGranahan & Swanton, 2017). Presently a crucial concern has been explored by scientists on cancer stem cells (CSCs), which attribute <1% population in the cancer heterogeneity and nonetheless have the ability for cancer initiation, self-renewability, and long-term proliferation potential. Collecting evidence has also explained that such cells could evade from present cancer therapies because of their inherent characters such as quiescent and drug resistance. Thus, CSCs signify the major subset within cancer, which is the main reason for cancer relapse and metastasis (Singh et al., 2017). Hence, occurrence of CSCs has a crucial challenge for cancer therapy with current clinical settings and needs substitute and advanced treatments. Tumor heterogeneity could be overcome by using phytochemicals having multifaceted properties to fight against severe ailments including cancer.

Phytodrugs: A historical view

Plants have been employed to cure several diseases from ancient periods. Ayurveda, Traditional Indian Medicine (TIM), and the Traditional Chinese Medicine (TCM) are most primeval (4500 BCE) hitherto living traditions. In the ancient time, the acquaintance of recruitment of correct plants, an exact time for their collection, and approach for drug synthesis with their specific implication were shifted casually from one generation to the next generation. The folklore system has recognized all parameters about the medicines and their specific applications in the disease situations. Such medicines had been synthesized as tinctures, teas, powders, poultices, decoctions, and another kind of formulations (Choudhari et al., 2020; Fridlender et al., 2015) that were the most prevalent approaches of drug synthesis until the 18th century. Sadly, none of them could be suitable according to the modern scientific definition of medicine.

With upgradation in organic chemistry and chemical assessment, an analytical examination of bioactive compounds of medicinal plants and herbal medicines was followed in the late 18th or early 19th centuries that opened the gates toward the isolation/purification and characterization of various active compounds of plants. This augmented the stride of drug discovery and directed to a miracle invention in the biomedical field. The first success that launched the first generation of drugs began with the separation of analgesic medicines morphine from the Papaver somniferum. Then, several well-known 20th century medicines had been obtained from plants such as salicylic acid, the precursor of aspirin (Salix sp.), cocaine (Erythroxylum coca), quinine (Cinchona officinalis), digitoxin (Digitalis purpurea and Digitalis lanata), and many more with medicinal and clinical efficiency (Butler, 2004; Newman et al., 2000). Over the period from approximately 1981 to the end of 2014, more than half of all authorized small-molecule drugs are derived from natural sources, where they aided as drug precursors, templates for artificial changes, and pharmacological probes (Newman & Cragg, 2016). This describes the various therapeutic potential of plants, which has been prevailed for thousands of years in traditional medicine.

Natural products

Plant-based products are the main source of biologically active components. In addition, their harmless or less toxic properties to healthy cells and better toleration have achieved attentiveness from the scientists and clinicians in the advance drug discovery field (Muhammad et al., 2022; Najmi et al., 2022). The structural diversity of fresh natural components is lifelong importance in drug development. It has been appraised that the plant kingdom has at least 250,000 species, among only 10% have been discovered for medicinal implications (Veeresham, 2012). Various natural components have exhibited potential functions against metastasis and cancer invasion (Parmar et al., 2008; Zughaibi et al., 2021). A few plant-based FDA-approved phytochemicals, such as tetrandrine, lycobetaine, curdione, vincristine, vinblastine, curcumol, monocrotaline, elliptinium, etoposide, gossypol, ipomeanol, taxol, indirubin, 10-hydroxycamptothecin, homoharringtonine, and colchicinamide, have revealed substantial anticancer properties (Singh et al., 2016). About more than 600 natural components have documented as an antitumor regimen. However, it has been summarized some well-known anticancer components, e.g., curcumin, indol-3-carbinol (I3C), resveratrol, kaempferol, epigallocatechin gallate (EGCG), and genistein.

Nutraceuticals

A nutraceutical is any constituent, which is considered as a food or part of food and is employed in cure or prevention of several diseases. The term nutraceutical is made of two words nutrition and pharmaceutical and had been named by Stephen DeFelice in 1989 (Kalra, 2003). As said by Stephen, nutraceutical is a food, food components or any nutritional supplement which have a certain health and therapeutic aids. The basis of nutraceuticals are plants (such as quercetin, luteolin, cellulose, lutein, gallic acid, perillyl alcohol, indole-3-carbonol, pectin), animals (e.g., choline, lecithin, calcium, coenzyme Q10, selenium, zine, creatine), and microbes (Saccharomyces boulardii, Bifidobacterium bifidum, Lactobacillus acidophilus, Streptococcus salivarius). The nutraceuticals have been part of daily life in developed countries. It is used in illness condition such as joint pain, insomnia, rheumatism, inflamed prostate, perimenopause, weight management, immunomodulators, and state of mind. Nutraceuticals are kind of isolated nutrients, nutritional supplements, and precise diets to genetically produced foods, flavored merchandise, and processed foods such as cereals, soups, and beverages that are commercially available in market. Nutraceuticals provide all the important ingredients, which should be in healthy diet. Nutraceuticals offer energy and nutrient supplements to body for maintaining ideal health. Nutraceuticals are also widely used in the food and pharmaceutical industries. Specific nutraceuticals are advantageous in maintaining healthy prostate execute, medicine for agitation, and sleep disorder (Sharma, 2009). Looking to medicinal properties of nutraceuticals, the plant-based nutraceuticals could be employed for treatment and prevention in cancer, though more studies are required against various cancers so that persons could add anticancer nutraceuticals in their