Modern Cancer Therapies and Traditional Medicine:An Integrative Approach to Combat Cancers

By Bentham Science Publishers

The advancements in molecular marker discovery, genomics, transcriptomics and proteomics in recent years have enabled researchers to develop targeted therapies against cancers. Cancer research and management is multi-disciplinary and multimodal. In addition to conventional chemotherapy and radiotherapy, targeted immunotherapy has also provided considerable success in the clinic. There is also scientific evidence on the impact of alternative therapies on cancer patients.
Modern Cancer Therapies and Traditional Medicine: An Integrative Approach to Combat Cancers summarizes the general aspects of cancer therapy and management. Chapters cover cancer medicine in two broad sections, the book presents comprehensive information on a diverse range of cancer treatments. The first section covers conventional molecular oncology and therapy including targeted therapies, immunotherapies, cancer signaling pathways and the use of computational techniques. The second section focuses on traditional methods of treatment including the role of nutrition, traditional medicine, Yoga and Ayurveda in cancer prevention and management.
The book is an accessible update of the state of the art in cancer diagnostics and therapy for students and academicians at all levels.

• Language: English
• Publisher: Bentham Science Publishers
• Release date: Feb 16, 2006
• ISBN: 9789814998666

Book preview

Evolution of Cancer Therapies

Sonali Verma¹, Gresh Chander¹, Deepika Bhushan Raina¹, Ruchi Shah², Rakesh Kumar¹, *

¹ Indian Council of Medical Research-Centre for Advance Research, Shri Mata Vaishno Devi University, Katra, J&K, India

² Department of Biotechnology, Kashmir University, J&K, India

Abstract

Cancer is commonly considered the Pathology of the Century assuming the associations of an endemic disease spread throughout the world. The beginning of the 20th century witnessed an improvement in the surgical techniques for tumor-excision, with the first abdominoperineal resection performed in 1908. Cancer treatment has been considered by its ups and downs throughout history, not only because of the side effect of treatments but also for the authenticity of cure and full remission, if any. In recent years, the first treatment of choice is immunotherapy with their significant therapeutic alternative. Nanotechnology is a new therapeutic replacement offering nanostructures for combining the treatment and imaging, targeted drug delivery, hyperthermia, and personalized, targeted therapy. Nowadays, gene therapy is contributing to a new approach to cancer treatment. These therapies can function independently or dependently with peptides, antibodies, folic acid, among others. In this chapter, we discuss the progression of cancer therapies and remedies, including immunotherapy, radiation, chemotherapy, surgery, nanomedicine, signalling pathway inhibitors and targeted gene therapy and their possible challenges.

Keywords: Antibody Therapies, Cancer Therapies, Cancer Vaccine, Cell Signalling Inhibitors, Hormone Therapies, Hyperthermia, Immunotherapies, Nanotechnology, Photodynamic Therapy.

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* Corresponding author Rakesh Kumar: Indian Council of Medical Research-Centre for Advance Research, Shri Mata Vaishno Devi University, Katra, J&K, India; Tel: [phone]; E-mail: [e-mail]

INTRODUCTION

The widely used techniques for cancer treatments include surgical excision, chemotherapy, radiotherapy, and immunotherapy. Since the 1930s, the traditional treatment of cancer is chemotherapy, where the term chemotherapy was invented by Nobel prize-winning German physician and scientist Paul Ehrlich. He started the treatment of cancers using alkylating agents [1].

Heidelberger developed the chemotherapy drug fluorouracil (5-FU) for solid

tumors. The first chemotherapy drug was invented in the year 1958 to cure the choriocarcinoma [1]. In the year 1960, with some advancement, the main targets for developing treatment were hematological malignancies. During the 1960s, all haematological malignancies and lymphomas were treated using the MOPP protocol (Mustargen, Oncovin, Procarbazine, Prednisone) that is based on procarbazine but no methotrexate as well as nitrogen mustard with vincristine, methotrexate, and prednisone [2].

In 1978, remarkable progress was made when the treatment of metastatic germ-line tumors was done by mixing bleomycin, vinblastine, and cisplatin [3-8]. The polychemotherapy experience of haematologic cancer has highlighted that different medications work against the malignant cells at different stages of the cell cycle. Since the 1970s, the understanding of the molecular alterations in malignant cells has improved. Consequently, during the 1980s, several medications with various modes of action were launched. Consequent discoveries and advancements led to the treatment using liposomes; wherein, the drugs are placed inside liposomes (lipid bilayers formed vesicles), reducing some chemotherapy side effects like cardiotoxicity [9].

The year 1990 ignited the launch of selective chemotherapy by scanning for specific molecular targets. Such advancements in conventional medicine and molecular biology research have led to an ongoing reduction in the mortality rate. Genomic sequence evidence revealed that certain cancer-related dysfunctions might be attributed to the irregular activity of certain protein kinases. In kinase inhibitors, the recent pharmacological trend has been observed [10-13]. The very first tumors treated by EMEA (European Medicines Agency) and FDA (Food and Drug Administration) approved drugs were renal tumors, hepatocellular cancer, and gastrointestinal stromal tumors.

In recent years, several tumors have been treated with many kinase inhibitors, and nowadays, clinicians prefer to combine these new targeted therapies with conventional chemotherapy. It has been reported and proved that in the advanced stages of cancer, chemotherapy plays a therapeutic role, including myelogenous leukemia and acute lymphoblastic, germ cell cancer, small cell lung cancer, ovarian cancer, Hodgkin's and non–Hodgkin's lymphoma, and choriocarcinoma. Although treatment is not always a permanent cure for these cancers, in some cases the overall survival has been significantly improved even at the metastatic stage.

Neoadjuvant therapy is another modality in the treatment regimen that prevents metastases and aims to reduce the size of the tumor. The organ-damage with this treatment is also reduced [14]. Neoadjuvant chemotherapy is specified for breast, lung, anal, rectal, gastroesophageal, bladder, head and neck cancer, and some types of cancer sarcoma.

Adjuvant chemotherapy has been recognized with therapeutic effects for many types of cancers, and cure rates are expected to rise with new effective drug combinations. In advanced countries, between 2005 and 2019, the evolution in cancer therapies regularly increases the rate of cancer survivors with a reduced death rate in cancer patients [15].

The first radical mastectomy was done in 1890 by Halsted and revealed that if surgical methods were used to remove the tumor, then cancer would be curable to some extent in aggressive stages, thus avoiding regional relapses. Since the development of the methods of mastectomy, various other scientists have tried surgery of cancer tissue. However, due to the developments in conventional radiotherapy and chemotherapy, the scenario is quite different. Nowadays, less extensive operations now have been replaced with radical surgeries [16].

The beginning of the 20th century is also known for the advancement in techniques of cancer surgery. In the year 1906, the first radical hysterectomy was performed by Wertheim, Miles performed the first abdominoperineal resection in 1908 [17], and the first lobectomy was performed in 1912 [18, 19], all carried out under oncological criteria. Modern surgeries have transformed significantly, non-invasive procedures such as laparoscopic colectomy (for the removal of colon cancer) has been replaced by Halstedian techniques [20, 21], radiofrequency ablation, video thoracoscopy, and radiosurgery techniques such as Cyberknife [22, 23]. Nowadays, one of the most promising therapy is immunotherapy for the treatment of cancers with positive results in clinical trials. The side effects of such treatments have been reduced using a combination of nanomedicine (nanotechnology) with standard drug delivery systems to get better results [24].

In the 19th century, the detection of cancer with X-rays as well as treatment with radiation was invented by Becquerel and Rontgen [25]. For the successful development of radiotherapy, Marie Curie contributed tremendously with her efforts. In 1898 the first cancer was cured with radiotherapy [26]. The charged particles are energized through a LINAC, or linear accelerator (basically, a vacuum tunnel). However, the evolution of advanced hardware and analysis tools permitted three-dimensional X-ray therapy, such as intensity-modulated radiation therapy (IMRT), by using a particular targeted region of plotting info from Computed Tomography (CT) scans. This advancement delivers a 3D-rebuilding, which assists in evading toxicity subsequently in the outline of the tumor, which is selected and separated from the normal tissue [27].

In the year 2003, with the advancements in radiotherapy, a specific type of intensity-modulated radiation therapy (IMRT) was used, known as TomoTherapy® system, where IMRT was implemented in the presence of CT for treatment. The CT makes it easy to trace the morphology of the tumor in the targeted region [28]. After the IMRT, another significant approach in the field of radiotherapy was the treatment with proton or helium ions. With the proton or helium ion radiotherapy specific types of cancers like uveal melanoma, chondroma (skull-based), chondrosarcoma, and cervical spine cancers could be treated. After IMRT, the advancement began in the scanning applications of radiotherapy, such as four-dimensional (4D) radiotherapy, which records the real-time arrangement of a tumor. This 4D advanced therapy uses live CT descriptions of the targeted tissue that recompense for any drive by the target tissue with the respiratory rate of the patient [29]. The kinds of radiation therapy are Image-guided adaptive radiation therapy (IGART) and Image-guided radiation therapy (IGRT).

Another combination method is the radiogenic therapy that causes cytotoxic agents to develop against cancer cells. This technique has been developed to use radiation to trigger promoters and thus activate the genes responsible for enzyme synthesis. These activated enzymes, in turn, activate the desired drug, and the drug's active form then kills the cancer cells [30]. In this chapter, we focus on the advancement of cancer therapeutic techniques along with several immunothe-rapeutic approaches and nanotechnology therapeutics, including accomplish-ments, disadvantages, and modern advancement in cancer therapeutics. The evolution of different therapies for cancer treatment is summarized in Fig. (1).

Fig. (1))

Systematic representation of periodic revolving facts in the field of cancer therapies.

TARGETED CANCER THERAPIES

Targeted cancer therapies aim to stop the growth of cancer by interfering with molecular targets with their specific molecules. Targeted cancer therapies are also known as ‘molecular-targeted drugs’ or precision medicines. Targeted therapy differs from other conventional therapies in many ways. Targeted therapies act directly on particularly targeted molecules that are associated with cancer, while standard therapies act on rapidly dividing healthy and abnormal growing cancerous cells [31]. Targeted therapies that stop tumor cell proliferation are also known as cytostatic therapies, while conventional therapy kills tumor cells and is known as cytotoxic therapies. The development of targeted therapy involves the identification of suitable targets that play a crucial role in cancer growth and survival. Targeted therapies are sometimes also considered a product of rational drug design [31]. One of the best approaches to identify a potential target is to compare the individual proteins in cancer cells with those in normal cells. Human epidermal growth factor receptor-2 (HER2) protein is one of the differentially expressed targets that is expressed at high levels on the surface of some cancer cells. Some targeted therapies are developed against HER-2 to treat breast and stomach tumors, overexpressing and overexposing HER-2. Another approach is identifying potential targets to see whether cancer cells produce altered (variant or mutant) proteins that drive cancer progression. A summative account of differently evolved therapies follows next.

Immunotherapies: This modality of cancer therapy activates or sensitizes the immune system to kill the cancer cells. Monoclonal antibodies recognize specific molecules on the surface of cancer cells. It works by binding the antibody to the targeted molecule, which destroys the cells that express the said targeted molecule. Targeted therapies are less toxic than conventional chemotherapy because cancer cells are more dependent on targets than the normal cells.

Hormone Therapies: This therapy kills or slows the tumors, which are hormone-sensitive and require specific hormones to grow. It works by inhibiting the hormone production in the body or by hindering the action of hormones. It is used for the treatment of breast and prostate cancers.

Signal Transduction Inhibitors: This therapy antagonizes the activities of signal transduction molecules regulating cellular proliferation and tissue growth and maintenance. In this therapy, an appropriate response is produced through a series of biochemical reactions initiated due to the inhibition of cell signaling.

Gene Expression Modulators: This therapy controls gene expression by changing the functions of proteins that are involved in gene expression.

Angiogenesis Inhibitors: Angiogenesis is a hallmark of tumor growth. This therapy stops the growth of new blood vessels to tumors, causing starvation and hypoxia in the tumor.

Immunotherapy

Our immune system is capable of recognizing several tumors and then eliminating them, and immunotherapy involves the use of the components of the immune system to eliminate various tumors [32]. For immunotherapy, the main components {antibodies (Abs), cytokines, and dendritic cells} of the immune system are targeted for cancer. Immunotherapy extends to medical and scientific practice with higher efficacy, focused targeted treatment, fewer side-effects, and better tolerance towards the therapy. Since the last few decades, immunotherapy is used for curing a wide variety of disorders. However, in the treatment of cancer, immunotherapy kills the malignant cells by sensitizing the immune system of a patient to kill the cancer cells naturally [33]. In the year 1967, the role of T cells in immunity was identified, which are involved in the immunotherapy against cancer nowadays as well. James Allison and Tasuku Honjo were awarded Nobel Prize in the year 2018 for their contribution to the field of immunotherapies. They successfully developed the inhibitors of cell cycle checkpoints which are used as targeted therapeutic agents [34].

Antibody Therapy

The antibodies were discovered by Emil von Behring, Paul Ehrlich, and Kitasato Shibasaburo in the year 1890 [34]. Antibodies act by binding to an antigen or a receptor on the cell's surface or by marking an antigen to be dismantled. A monoclonal antibody targets a specific antigen and clonally expands itself via the multiplication of plasma B cells in order to attain a medically effective dose of treatment [35]. The antibodies are used in the treatment of various disorders like infections, growth of tumors, and autoimmune disorders [36].

Primarily immunotherapy is performed with the usage of antisera obtained from horses and sheep where a combination of antibodies from the initiation of several B cell replicas or clones, so-called Polyclonal Antibodies (PAbs). For the treatment of infections like diphtheria and tetanus, serum therapy has been used where antisera obtained from animals were used. In the year 1926, Felton and Bailey found untainted antibodies. Nonetheless, the structure of the antibody became known and identified by Porter and Edelman in1972 and was awarded the Nobel Prize [34].

The use of antibodies for therapy, scientists identified that the moved defense was transient because, like vaccination induces long-term memory in the treatment of any disorder [37]. In addition to this, it is frequently experienced anaphylactic retorts that were infrequently lethal and which significantly abridged their usage in therapies [38]. Nevertheless, these glitches did not avert PAbs from being used positively in diagnostic systems and even in precautionary treatment therapies. The best example is ant-tetanus, anti-snake venom, and anti-Rh+ gamma globulins which are still rummage-sale in treatment [39].

In the year 1997, the first monoclonal antibody (Rituximab), trastuzumab (Herceptin), permitted by the FDA used for the treatment of various cancers by targeting the B cells (immature) for the exclusion of natural killer cells. The drug trastuzumab which was used to treat breast cancer cells were developed as a conjugated antibody for the reason that they start their act after attaching to another agent (radioactive or chemical), which will further help in the destruction of malignant cells [40].

Interferons and Cytokines

Cytokines are naturally occurring proteins that are small and secreted by cells that constitute the immune system. They are critical in moving between cells of the immune system as well as other cells of the body [41]. In 1957, the interferon-alpha (IL-I) was the first cytokine identified by Isaacs and Lindenmann, whereas IL-2 was identified in 1976 [34]. These interferons are the growth factor of T-cell. From the clinical trial studies, it was proved that T-cells able to control the growth of the tumor with a significant decrease in the progression of a metastatic tumor with the regular production of T lymphocytes called immunostimulatory cytokine. In 1991, the US FDA accepted and permitted the use of interleukin-2 as a targeted immunotherapeutic treatment of cancer [34]. The paradigms of cancer treatment were changed after immunotherapy. However, the main drawback of immunotherapy is the lack of response rates due to the presence of the host's pre-existing anti-tumor immunity. The chemotherapy drugs used in cancer cure have immunosuppressive effects. It has been reported that the majority of cancer cases were diagnosed in immunosuppressed individuals [42]. From all the tumour-infiltrating cells, the T-regulatory cells are the most important in the obliteration of the immune system, indorsing immunosuppression after the secretion of immunosuppressive cytokines. Therefore, by depleting several macrophages, cancer-targeted therapies were invented by targeting tumor-infiltrating macrophages [43].

Cancer Vaccine Therapy

Undoubtedly there is no single medical novelty that has had an additional noteworthy influence upon the medication and universal well-being than the origination and expansion of immunizations. Impartial as our immunity works continuously to avert contaminations as well as infections, shielding us from possibly damaging microorganisms (bacteria, viruses, and parasites) the immune system also plays an essential role in cancer prevention. It is probable to augment this purpose either by averting contagion or by educating immune system cells to identify and slay malignant cells after they rise in the body [34]. To date, there was a wide variety of cancer prevention vaccines the human papillomavirus (HPV) and (hepatitis B (HBV)), together with which prevent infection by carcinogenic viruses. The influence of cancer viruses is drastically increasing day by day by providing evidence and deterrence through immunization, which is the most significant and actual method of dropping increased cancer prevalence. The types of cancer vaccines are autologous and allogenic [34].

The autologous vaccine is a personalized cancer vaccine designed from an individual cell (malignant or immune cell). In the development of the autologous vaccine, the patient’s cells were processed in-vitro and transferred back into the circulatory system, then treated cells identify their targeted cells and start responding against the disorder by generating their immune response [44]. This type of therapy with their memory cells immediately responds if cancer cells relapse soon.

Allogenic vaccines are non-self-vaccines which is grown under laboratory conditions. These types of immunization processes are very tough, but the success rate is significant at a low cost. The purpose of allogenic immunization is to activate immunity against particularly aggressive malignant cells, with the certainty that these types of cancer cells are recognizable. Despite various advancements in the evolution of cancer therapies, no approach has yet been proven to be very effective in the development of allogenic immunization [34].

All the above-discussed cancer immunizations are founded on whole cells, but there has been an approximate achievement in emerging cancer vaccines from cancer molecules such as proteins or DNA. For the treatment, the molecules have been directed alone or bounded with suitable carriers (viruses, plasmids, or special nanoparticles) [45]. Numerous running clinical investigations are linking these types of vaccines with their goals that comprise melanoma, breast cancer, and prostate cancer [46].

Primarily in the field of vaccine clinical trials, there was a great achievement concerning multiple malignant cell-specific neoantigens that confirms a high patient-specificity [47]. Neoantigens are antigens that encoded by altered genes and exist on malignant tumor tissue, meanwhile, during the past few decades, they are widely considered due to their influential character in cancer treatment as immunotherapy [48]. As a consequence of tumor-specific somatic alterations, neoantigens do not exist on the exterior of benign cells [49].

Numerous preclinical, experimental studies have previously proved the possibility and efficiency of neoantigen-targeting cancer therapy in the form of vaccines for the treatment of melanoma, colon carcinoma, glioma, melanoma, and sarcoma [50]. Even though still in very initial phases, the combination of neoantigens-based rehabilitations with other kinds of immunotherapy, such as inhibitors of cell cycle checkpoint, as well as conventional dealings to cure cancer, seems promising [50].

Nanotechnology-Based Therapies

Cancer therapies currently involve three main types surgery, chemotherapy, and radiation, all these therapies damage the normal tissues and involve the incomplete removal of the cancerous cells in the body. Nanotechnology adds the technology to target the chemotherapies directly and selectively to cancerous cells and neoplasms in surgical resection of tumors and increases the efficacy of therapeutic radiation and current treatment technologies [51]. These therapies decrease the risk of patients and add to the survival of a patient. With the help of nano-scale and nano-structured based technologies, cancerous cells and the associated biomarkers can be sensed. If compared to the standard therapies, nanoparticles show six different advantages in cancer treatment and its diagnosis, which are as follows:

Nanoparticles can be unifying in a particular size and with a surface, characteristics to penetrate the tutor with the help of a passive targeting mechanism (enhanced permeation and retention effect.

These nanoparticles can be incorporated to target tumor cells with the help of an active targeting mechanism in which the tumor cells by surface capabilities with its biomolecules gets attached to the tumor-specific marker.

Nanoparticles can be arranged in such a manner that they can penetrate tumor cells and some physiological barriers.

These can raise the plasma half-life of chemotherapeutic drugs which are extremely hydrophobic.

They usually guard the therapeutic burden from biological degradation.

They can be used as theragnostic nanoparticles which provide platforms for therapeutic applications and multifunctional combined imaging [52].

The cancer nano therapy field has provided certain advancements by increasing vector functionality and tumor targeting. Till time, there are many barriers in drug and gene delivery, but with the help of a nanoparticle multi-functionality system, these barriers can be quickly addressed. The evolving advancement in nano therapy helps in detecting heterogeneity and biological diversity that are present with most of aggressive cancers. New nano therapy technologies are used to target cancer stem cells which are linked to treatment resistance [53]. Their unique interaction with the nanoparticles of the immune system is being assessed as therapeutic vaccines, targeted monoclonal antibody treatments, and activators of cell-based immune therapies. Nanoparticle design has grown drastically in the current times and has provided the platform for addressing the obstacles in cancer therapy [54].

Photodynamic Therapy

Photodynamic therapy (PDT) has developed as a significant therapeutic method to treat infections, cancer, and other diseases [55-57]. It is a technique of phototherapy involving light and a photosensitizing chemical substance, used in conjunction with molecular oxygen to elicit cell death (phototoxicity) [58]. Photodynamic therapy is generally performed as ambulatory surgery and may be constant and used by combining with other therapies, such as chemotherapy, radiation, and surgery [55]. PDT seems to be a treatment technique for numerous types of ailments including apparent types of tumors such as head and neck tumors, basal cell carcinomas, and endoscopy-accessible tumors (oesophageal and lung cancers) [55, 59, 60].

Despite plenty of advantages, PDT has some disadvantages. Precaution of light exposure is required to take to the patient treated with photosensitizers (PS) because patients treated with PS might get sensitive to light. People treated with photosensitizers are water-soluble molecules. Therefore it is easy to inoculate into the body. PDT is used to cure only superficial tumors such as oral cancer, skin cancer, nasopharyngeal cancer due to its inadequate light penetration in the tissue (600to 700 nm), it can penetrate only up to 10 mm of the skin to influence the tumor site [61-63]. In photodynamic therapy, nanoparticles have been recognized as a beneficial agent due to their absorption capacity, which is 4-5 orders of magnitude more than predictable photo absorbing dyes [64]. To capture the water-insoluble anticancer drug 2-devinyl-2-(1-hexyloxyethyl) pyro pheophorbide in the non-polar core of micelles produced silica nanoparticle is used. There is a decrease in cell survival percentage when HeLa cells make singlet oxygen near-infrared light radiation [65]. Preclinical studies govern additional translational values of PDT treatment by using nanoparticle-loaded photosensitizers before their use in clinical settings.

Hyperthermia

Hypothermia is a therapeutic technique comprised of heating of body or local tissue/tumor to prevent cancer cell proliferation. The temperature of the body is raised to 41-43⁰C through the application of ultrasound or electromagnetic energy to sensitize the cells for additional therapies for a definite period. Currently, hyperthermia is used as an adjunct therapy to chemo and radiotherapy. Cells become sensitized to therapeutic agents such as chemotherapy and radiation when they are heated above their physiological temperature. Temperature above 43⁰C causes severe damage to the cells and results in tumor cell death by the processes known as thermal ablation. The process of thermal ablation eradicate whole tumor mass without causing any damage to the vital structure, which is a great success indeed. This condition is generally significant for patients with inadequate reserves function of the tissue. Hyperthermia techniques make use of radiofrequency, microwaves, and ultrasounds, which can be used locally to focused target the tumor and is found minimal invasive. Blood flow rises due to slight heat in the tumor, permitting chemotherapy to apply a better effect on cancer cells. Heat also reduces the demand for oxygen in the tumor cells by depressing the target cell metabolic activity and increase the tissue oxygenation, due to which hypothermia is one of the most effective accessible radiosensitizers [66]. Studies and clinical trials led under quality assurance guidelines have revealed that during the treatment of numerous types of solid tumors, melanoma, including breast cancer and sarcoma, locally advanced cervical cancer the survival rate of hyperthermia treated patients are more as compared to the patients who take chemotherapy and radiotherapy only [67, 68].

To improve the heat delivery nanotechnology may offer an initial chance, e.g., in deep Brain tumors it is challenging to attain highly focused ultrasound energy transfer due to skulls electromagnetic barriers. Iron oxides are used by magnetic fluid hyperthermia (MFH) as a heating source due to their ability and outstanding magnetic properties [69]. Magnetically mediated hyperthermia is of two types depending upon their route of administration, direct intratumorally injection hyperthermia, and arterial embolization hyperthermia.

By using magnetic resonance imaging (MRI) magnetic nanoparticles can also be traced instantly, and by the high frequency alternating magnetic field application, these nanoparticles are heated selectively. Cancer cell death occurs at the temperature of 43oC and above due to the induced heating of nanoparticles indulgence with magnetic energy. In animal models of glioma and prostate cancer, significant antineoplastic magnetic fluid hyperthermia treatment effects were initially observed, and prostate cancer [70, 71]. To treat the glioblastoma multiforme and prostate cancer, clinical trials of phases I and II with thermotherapy using magnetic particles have been conducted subsequently. Magnetic hyperthermia has been reported with some limiting factors, comprises of uneasiness of the patient at high magnetic field strengths and unstable intratumorally heat distribution [72]. While treating cancer patients some tissue with hyperthermia it may feel scalding and cause discomfort or pain, burns, blood clots, swelling, blisters, and bleeding, and whole-body hyperthermia may cause vomiting, diarrhoea, and nausea. Sometimes in very rare cases, it can damage the blood vessels or heart [73]. The usage of magnetic hyperthermia to activate drug issues has also been proved as possible tactic for the treatment of cancer.

Magnetic nanoparticles coated with a thermo-responsive polymer poly-n-isopropyl acrylamide were introduced by Purushotham et al. [74]. Drug release and concurrent hyperthermia were achieved in-vitro with these nanoparticles by therapeutically appropriate quantities of doxorubicin at hyperthermia temperatures. With the support of these nanoparticles at hypothermia temperature therapeutically appropriate quantities of doxorubicin, an in-vitro drug was achieved. In rat models, in-vivo targeting of nanoparticles loaded with doxorubicin inoculated through the main hepatic artery to hepatocellular carcinoma followed by MRI examination. Nanoparticles have the benefit of being able to scatter light or captivate near-infrared (NIR) absorptions due to which temperature rises in where the nanoparticles have been embedded in the tissue. Through biological chromophore and water, the area of the electromagnetic spectrum is prominent for nominal absorption [75]. Therefore, in biomedical applications, NIR light is a better choice as a trigger because it has the best penetration of tissues at those wavelengths due to their low absorbance.

Near the infrared region, water and haemoglobin have their lowest absorption coefficient around 650-900 nm. By using (FDA class 1) microwatt laser sources NIR light has been revealed to travel at least 4 cm to skull/brain tissue or 10 cm through breast tissue and deep muscles and 7 cm of new-born brain/skull and muscle at a higher power level (FDA class 3) [75]. The photothermal ablation of solid tumors is also considered for the use of Au nanoparticles (nanoshells)/SiO2 NIR absorbing tags [76].

Nanoshells afford less absorption (30% scattering for SiO2/Au 70% absorption) than Au/Au sulfide NIR-absorbing nanoparticles (35-55 nm) (2% scattering and 98% absorption) as well as probably better tumor diffusion [77]. Hollow gold nanoparticles are lesser in size than SiO2/Au and are added one used in near-infrared, which enhances the chance of reaching on the targeted tumor cell due to long blood circulation half-life [78].

In a research work was done by Maltzahn et al, in 2009 in his finding he proved that protected gold nanorods show good spectral bandwidth, extended blood circulation half-life in comparison of nanoshells, more photothermal heat generation, and extended circulation half-life when compared to gold nanoshells, and nearly about absorption of two-fold more X-ray than a clinical iodine contrast agent [79]. To attain tumor targeting in medulloblastoma cells, anti -HER2 antibodies play a significant role with NIR- absorbing particles [80]. In monocyte cell lineage nanoshells have been loaded. Nanoshells have been loaded into cells of monocyte lineage, which behave as carriers. In a tumor’s hypoxic microenvironment, photo-induced cell death could be caused by nanoparticle-loaded macrophages when human breast tumor induced in nude mice [81].

Recent studies are focused on the functioning of engineering more efficient NIR-absorbing nanomaterials with targeting moieties. In comparison with recent accessible non-invasive measures with abilities to raise the temperature of target tumors, the main problems of NIR-absorbing nanoparticles and magnetic rise from their inherently invasive nature as well as tissue damage from the comparatively indiscriminate nature. These therapeutic techniques are emerging in the biomedical research community due to their related concern in acute and effectual intracellular acceptance and its long-term properties of inorganic nanoparticles cytotoxicity [82-84]. Various studies show that the toxicity of hypothermia application is low, despite the development of designed nanoparticles at a higher rate [85]. Statistical data specify that shape, size, surface chemistry, and crystallinity strongly affect the inorganic nanoparticle internalization mechanism by cells, their potential toxicity, biodistribution. Metabolism shows the significance of nanoparticle interaction with tumor cells.

Role of Gene Therapy in Cancer Treatment

The idea of gene therapy was primarily proposed in the 1970s, but due to the deficiency of facilities, the awkward nature of the testing was not sufficiently advanced until the early 1980s. In 1989 the first clinical trial was officially approved, and due to the forthright success of gene therapy, several viral vectors quickly moved to clinical settings [86]. In 2018, World Health Organization declare cancer as the second leading cause of death, 9.6 million peoples die in the same year (WHO, 2019). To fight with this deadly disease, the applications of gene therapy and the challenges of cancer proliferation have been instrumental in the advancement of novel approaches and strategies. However, still, the efficiency of the planned tactics fallen short kin clinic to bring complete possible gene therapy. Still, it is a challenge to find a way to deliver these effectors to the targeted tissue and cell, despite the overabundance of gene modulation methods, e.g., RNA interference, gene silencing, gene, and genome editing, and antisense therapy [87]. Gene therapy is the technique that aims to treat ailments by introducing antisense oligonucleotides, small interfering RNA, RNA, and DNA, into definite target tissue and cell to eliminate the infectious abnormalities and re-establish missing functionality. Without creating any undesired side effects, therapeutic gene material is given to specific target cells using a systematic vector. Four types of carriers are recognized for gene application delivery, i.e., recombinant proteins, inorganic nanoparticles, organic cationic compounds, and Viral carriers [88, 89].

Delivery of therapeutic nucleic acids such as miRNAs or siRNAs, genes, oligonucleotides, to cancer disease can be handled by restoring the expression of tumor suppressor gene or silencing oncogenes [90, 91]. Furthermost, these methods (e.g., RNA interference (RNAi), gene editing, antisense therapy) target gene modulation [92, 93]. Gene therapy immunization, mainly antigen receptors (CAR) in T cells based on treatments signify the number of therapeutic policies in clinical trials. Although the viruses are effective carriers, there is still a limited cargo capacity of DNA, which causes toxicity and immunogenicity and their production is expensive. Deprived of genetic drugs size limits an artificial drug delivery system to avoid precise immune responses and may carry developed quantities of material. The primarily targeted gene suppressors for the replacement of gene therapy are p21, TP53, and PTEN [94-96]. Replacement of gene can be accomplished by modifying the alteration of gene mutations into their wild form, transduction of gene, and preservation of constancy and full gene appearance [97]. TP53 is primarily targeted because of its vital role in the regulation of the protein cell cycle, autophagy, apoptosis, and DNA repair [98]. In the year 2003, the gendicine was the first commercial gene therapy invention and is a p53 recombinant human adenovirus approved for neck and head squamous cell carcinoma approved by the Chinese Food and Drug Administration in collaboration with SiBiono Gene Technologies [99]. Nuclear targeted delivery in the presence of nucleotide sequences in DNA or localization of nuclear signal is the approach to advance the DNA entry into the nucleus.

Oncogene Silencing via RNAi

There is decreased expression of specific genes in the transfer of nucleic acids into tumor cells in gene silencing [100-103]. Gene silencing treatment is generally proficient by presenting shRNA or siRNA in tumor cells intended to target a precise balancing sequence mRNA of a selective gene, by blocking protein synthesis or inducing its degradation [104]. There are some new targeted treatments by using RNAi tumor oncogenes such as KRAS or cMYC and drug resistance genes such as multi-drug resistance [105, 106]. There are various limitations in RNAi and to overcome these limitations, researchers are approaching various techniques, the foremost limitations are dissipation in circulation, target specificity, escape of endosomal and cellular internalization [107].

Inhibitors of Signaling Cascades

The genetic and epigenetic modification operates the cancerous cells by multiplying and escaping mechanism, which helps in controlling their survival and transfer. This modification helps in mapping the signaling pathway that controls cell growth, cell death, cell motility, cell division and with these modifications, deformation of a signaling pathway is done which triggers the growth of cancer [108]. These include tumor microenvironment, inflammation, and angiogenesis. Cancer also grows due to dejections in the signaling pathway. Many studies have shown that cancer cells respond to old drug treatment by adapting their signaling pathway and cross-linking to maintain their function [109]. Various studies targeted the inhibitors of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathway as a modern therapeutic approach which explains how alterations of signaling pathways are inhibited through targeted inhibitors. Signal transduction inhibitors kill the expressed molecule that controls the cell growth process, differentiation, and survival. Signal transduction inhibitors include targeted receptors and molecules, e.g. epidermal growth factor receptor and intercellular biochemical molecules [110].

Cell signaling or signal transduction regulates essential cellular activity through various complex reactions. Many researchers have explained the PI3K/AKT/mTOR pathway in humans. It involves the complex series of chemical reactions that activate cells to move or not move in the G1 and G2 transition phase through the reproductive cycle. This pathway is involved in 70% of cancers [111]. It has attracted the attention of many researchers to stop or slow cancer progression using PI3K pathway inhibitors (Phosphoinositide 3 kinase enzymes are phospholipid kinases). PI3K helps in the transmission of signals across the cell membrane. There are only four PI3K inhibitors that are used for cancer treatment which are approved by FDA, which are named as, Idealisib, Cpanlisib, Duvelisib, Alpelisib. Alpelisib is used for the treatment of breast cancer [110]. These inhibitors are often given in combination with other chemotherapeutic agents and inhibit all four PI3K isoforms. The signaling pathway helps in maintaining the normal physiological function. There are many efforts which are made to develop therapeutic agents to target the cancerous cells. Many signaling inhibitors are under clinical trials, but no particular drug is used for clinical use [111].

CONCLUSION

This study has tried to recapitulate the evolution of the cancer therapies available today. However, with the significant approaches in the field of cancer biology, various types of novel therapies were studied in the last few years. In addition to ongoing therapies like chemotherapy, radiation therapy, surgery, hyperthermia, immunotherapy or photodynamic therapy, novel therapies with improved curability rate are now at peak phases of growth and expansion which trying to reduce the drug noxiousness in other organs of body and upsurge effectiveness by directing the process of tumor angiogenesis, by sightseeing gene therapy, or using nanostructures for analysis of cancer cells or as a therapy to cure the cancer cells. Nanotechnology contributes to the development of novel products. These products are used in conjunction with other biomolecules (anti-tumoral drug folic acid, albumin, antibodies, aptamers) to target malignant cells.

Nevertheless, previous research studies provide the fact that competition against cancer is not a casual task. Numerous cancers cells are not able to respond against traditional cancer rehabilitation therapies (surgery, chemotherapy, and radiotherapy,) which are frequently the lone way to abolish malignant cells. This might also be factual for the novel therapies incoming nowadays to the clinical trials. Abundant studies are obligatory, but these novel personalized ways of cancer treatment are initial steps to confidence for patients waiting for a fruitful treatment of