Ayurveda & Bioactives as Adjuvant for Dna Modulation in Cancer Treatment & Adverse Drug Reaction [ADR] – A Glimpse of Traditional Indian Nanotechnology

Bioactives such as Curcumin and Quercetin and herbs such as “Tulsi”/ Holy basil [ Occimum sanctum L.] can provide relief from Adverse drug reaction [ADR] caused by chemotherapy in cancer patients. About 50% patients face moderate ADR issues such as nausea, vomiting, headache, and fewer [20-30%] serious ones [hair loss, loss of fertility and immunity]. The growing recurrence or resistance of cancers to chemotherapy and antimicrobial resistance [AMR] are other emerging challenges in addressing the global cancer burden, among the top causes of death. Two targets of herbal/ bioactive actions include topoisomerase that affects cell replication and telomere length and it may reduce resistance/ recurrence also. Patients with special conditions the old, children and less developed countries with low health budgets can especially develop from it.


Introduction
Cancer is the 2 nd leading cause of death in the world causing 10 million i.e. 16% of global deaths in 2018 vide World health Organisation data. [1]There were 2 times as many new cases reported in 2022. [2]About 1 in 5 people develop cancer in their lifetime, approximately 1 in 9 men and 1 in 12 women die from the disease, the study says.The new estimates available on IARC's Global Cancer Observatory above show that 10 types of cancer collectively comprised around 2/3 rd of new cases and deaths globally in 2022.Data covers 185 countries and 36 cancers. [2]ncer prevalence are low among many poor/ middle income nations in Africa & Asia as per that map and developed world needs to explore its causes and best practices to follow.ancer was rare in the 20 th century to occur few hundred or thousand cases annually in a city but is common today that it is common among every lane in cities.In fact, its is 3 most leading cause of deaths in India among non-communicable diseases with 8% of all deaths, after cardiovascular [28%] and respiratory diseases [10%], among the non-communicable diseases that together comprised 61% of all deaths in 2016 in India. [4]There are limitations of various cancer treatment prevalent regimes so search for new drugs is ongoing continually, including immunotherapy recently that has new promises as well as new problems despite the initial hope that it will avoid majority of the adverse drug reactions [ADR]   caused by chemotherapy, the dominant treatment type. [5]Hence, search for safer medicines with lesser ADR is also continuing, including Botanicals. [6]mplete cancer cure by Ayurveda medicine alone was a recent news and scientific publication [7] .It wsas a case of 51year-old female patient, diagnosed with high-grade non Hodgkin lymphoma of type "Diffuse large B-cell lymphoma" [DLBCL] confirmed by by PET-CT scan.She was started with Rasayana [special chemicals, vide Ayurvedic literature, for body rejuvenation/ anti-ageing] regimen.
Significant clinical improvement and regression in tumor size in this patient after treatment as will be discussed later.This, along with few other cases mentioned further triggered this article to explore the value of Ayruveda, the prevalent

Methodology
We enlist a few cases we have directly observed in the past decade with Ayurveda either solely or in combination with modern treatment [mostly chemotherapy].We then enlist the major medicinal plants i.e. herbs used in these treatments and their bioactive ingredients from literature.We enlist their pharmacological actions as corroborative evidence of potential utility in cancer treatment.Finally, we mention some literature evidences regarding the safety of using these herbs and metal ash/ oxides in cancer treatment.

Cases Observed
Besides the above case have observed the following cases treated with Ayurveda along or with Chemotherapy.Chemotherapy was stopped by relatives after 3 and 6 cycles as the 3 rd and 5 th patient could not sustain the sever ADR.
Patient no.7 had mild COVID-19 fever& recovered at home 5 months before death.

Discussion
The published case of Lymphoma patient cured by Aurveda mentions the "rasayana" [alchemy/ elixir/ rejunevating chemicals] regimen consists of many bhasmas [incinerated ash of metals] and herbo-mineral formulations. [7]No the patient or others treated in that clinic or elsewhere in India showed any toxicity signs.After treatment of 23 months the hematological and biochemical values restored to normalcy.Significantly no adverse effects were reported, testifying the safety of the metallic formulations.Remarkably, biopsy after-treatment showed no evidence of lymphoma, The quality of life and physical performance of the patient improved with weight gain, unlike in the chemotherapy/ radiotherapy.The rasayana treatment can be administered orally, without injections or hospitalization at much lower cost-at10-20% of the modern medicine.Conventional standard of care will improve therapeutic outcomes and the anecdotal evidence warrants further clinical studies.

Adverse effects and herbal adjuvants
ADR is a major issue faced by many cancer patients on modern treatment that commonly includes interstitial pneumonitis, lungs infections, colitis, diarrhea, and endocrine disorders as per USA data. [5]Another, early and large study says that long-term adult survivors may face more physical limitations [53% compared with 21% for controls without cancer]. [32]Muscle activity may be most likely be impaired and these survivors may face limited participation in social events, sports, shopping [31% vs 13% reported by controls].
An earliest large cross-sectional study in Germany of survivors 1 to 5 years after the diagnosis of stage I or II breast cancer who were disease-free, reported that the most frequent physical symptoms were general aches and pains [70%], muscle stiffness [64%], and joint pain [62%]. [33]Women who were prematurely postmenopausal and those who received chemotherapy had a higher risk of sexual dysfunction.
In India, a study of total of 500 patients who developed ADRs due to cancer chemotherapy during 2018-2019 in Uttarakhand state, reported 665 ADRs. [34]Commonest ADR was anemia was followed by nausea/vomiting and leucopenia.The most common drugs implicated were cisplatin, paclitaxel, carboplatin, and doxorubicin.Naranjo's scale showed 92% of ADRs as probable and 7% as possible.About 80% of ADRs were of moderate [level 3 and 4] severity, 11% mild [level 1 and 2] severity, and 8.2% of level 5 severity.Preventable ADRs comprised of only 27% and 73% not preventable, which is a cause for concern to address these.Another study from Bihar state in India however mentioned contradictory observation-with 49% patients complaining hair loss-alopecia, 27% nausea, vomiting & burning sensation, 24% of constipation. [35]e common ADRs as indicated in the 1 st Indian study above include nausea, vomiting [20%], diarrhoea [5%], headache [5%], hair loss [5%]. [34]The 2 nd Indian subsequent study also mentioned these but with contrasting frequencies. [35]These ailments can be treated with common Ayurvedic/ herbal remedies such as Ginger as its phytochemicals Gingerols and shogaols show biological activity, like anticancer, oxidative stress reduction, antimicrobial, anti-inflammatory, and anti-allergic to multiple central nervous system activities [36].Loss of both fertility [23] and immunity [5][37] are major challenges.

Diet relation to cancer recovery and recurrence
There was relation "diet" mentioned earlier [32] but "healthy diet" is promoted now through Government advisory such as in the USA [ Box 2]. [41]In fact, there is increasing trend and research globally towards complementary and alternative medicine [CAM] as evidenced as a study in Norway [42] comprising 315 women and 153 men with a response rate of 67% Box 2. Healthy diet advisory for Cancer survivors, USA [41] Recurrence of cancer is a risk is faced by considerable proportion of the cancer survivors and varies by cancer type, besides age of the patient and other factors.About 7-13% of breast cancer patients developed recurrent cancer within 5 years of adjuvant or neo-adjuvant treatment, with increasing risk seen for increasing breast cancer stage. [43]The study mentions prostate cancer has higher rate of 25% recurrence in patients who have had radical prostatectomy.Lung cancer recurrence has wider range [30-75%].Adenomas, which are associated with colorectal cancer, have been reported to recur in 40-50% of patients.Colon cancer has been found to recur in approximately 33% of patients with stage II and III cancer.Polyphenol rich diet may reduce the risk of cancer recurrence, the authors argued and other too have demonstrated earlier. [44]The therapeutic action of polyphenols is enhanced or modulated by the gut microbiota and it is diet dependant. [45]lyphenols are among these supplements and can neutralize free radicals turning them in less dangerous and thereby, stopping side reactions.Polyphenols have broad applications such as the treatment of cancer or inflammations, anti-aging aims in cosmetics or nutraceutical purposes.Moreover, polyphenols are known to be nootropics, owing to be helpful in several functions of the brain, such as learning, memory, attention or motivation, thereby protecting the brain against neurodegenerative diseases. [43]ug interactions Exploring integration of herbs or Ayurveda [Rasayana] therapy or botanicals with chemotherapy/ radiotherapy to improve efficacy and reduce ADR is suggested by scientist in USA also. [25]Table 4 depicts these, with some interaction but overall benefits.

HERB BIOACTIVES TARGET/ MECHANISM PLACE, YEAR REMARK
Turmeric Curcumin cytochrome P450 USA, 2020 Interference, but can modulate side effects [25] Ashwagandha & Asparagus Withanoloide, Saponins Pro-inflammatory cytokines, Hematological Homeostasis Pune, 2020 evaluated as safe, desirable therapeutic adjuvants for cancer [6] Heart leaved moonseed Berberin, Tinospoine Odisha, 2012 Similar effect to Doxorubicin [46] Triphala Polyphenols [Flavanoids], Gallates, Glycosides Cytotoxic to cancer cell lines, protects normal ones, rejuvenates USA, 2017, 2023 Adjuvant therapy to Radiation and Chemotherapy, [25][29] [31] Table 4. Ayurvedic medicines/ herbs as adjuvants in chemotherapy A review of 115 articles on internet, using keywords, breast cancer, and medicinal plants, aggregated 64 therapeutic targets from 35 different plant species. [47]Among the molecular targets, 51 % [33/64] caused apoptosis and 37 % [24/64]   demonstrated cell proliferation activity.The review provides evidence of data suggesting that 17 % therapeutic targets have carcinogen inactivation activity, 10 % have precancerous growth prevention activity, 9% have mutagenesis and gene expression activity, and 4 % regulate toxic metabolism.The authors further argue that Ayurveda/ herbal medicines can be beneficially incorporated with chemotherapy, the predominant regime to reduce ADR & improved recovery, better health of the survivors.A key feature of Ayurvedic medicine is its "Polyherbal" nature with synergistic effect and pre-empting the emergence of resistance. [48]The lower ADR makes them suitable for patients with special conditions such as children or elders.This is crucial as for instance, researchers are predicting that the number of persons over the age of 65 years diagnosed with cancer each year will double by the year 2050 in USA, and will quadruple among those aged ≥85 years then. [32]Similar pattern may occur in the developed nations/ globally due to wealth increase all over.
Govt. of Victoria in Canada enlists popular botanicals used in CAM and their interaction with cancer drugs.Of these, Turmeric is said to make no effect on the treatment while Black pepper, Garlic, Guggul tree gum, Licorice may influence the chemotherapy treatment outcomes, its cautioned. [49]However, another review suggested that Turmeric may influence negatively the outcomes. [50]Nevertheless, yet another analysis did not find serious ADR of combined use of herbals with chemotherapy but only 8% ADR as fatal and 5% avoidable. [51]Ginger or turmeric were not claimed for serious ADR and integrative therapy was recommended for the best outcomes with phytovigilance.This was based on the analysis of

DNA modulation
The anti-cancer activity of Ayurvedic herbs is ascribed to either as topoisomerase inhibitors poisons such as Phyllanthus amarus Schum and Thonn.[bioactive Phyllanthin] or Nothapodytes nimmoniana [J Graham] Mabb.{syn.Mappia foetida [Wt.]Miers, bioactive Camptothesin}. [19] Yet another potential emerging mechanisms is GLP-1 Agonist like Semaglutide, basically used in diabetes similar to the famous branded drug "Ozempic" is found useful in treating cancer also. [55]It inhibits the cancer cell proliferation by the cAMP-PKA pathway, acting as molecular brake on the uncontrolled cell division, thereby impeding the relentless expansion of malignant cells [56] .Impaired glucose metabolism may be a causal factor behind cancer so its is important to reduce sugar and glycation/ lipoxidation end products [AGE/ ALE] they argued and cited research showing that 20-40% of the cancers are diet dependent and preventable. [57]Cinnamon, the routine Indian spice is a GLP-1 agonist and found useful in treating cancer, besides diabetes. [58]Some other pathways of action include apoptosis as enlisted earlier and anti-oxidant activity thereby reducing the stress viz.reactive oxygen species [ROS], to help smooth physiological functioning. [59][60] [49] Many other herbs in India and Africa/ tropics are also found to be useful in addressing cancer e.g.Kalmegh [ Andrographis paniculata Nees, bioactive Andrographaloide, [61][62][63] [64] ] and Black cumin [Nigella sativa L., bioactive Thymoquinone]. [65][66]In fact, the former is found to even overcome the Gemcitabine Resistance through Regulation of ERBB3 and Calcium Signaling Pathway in Pancreatic Ductal Adenocarcinoma. [67]The ever-growing resistance to synthetic molecules is a growing concern [68].We suggest that herbals can possibly address it with more research.

Innovations-local and Global
Complete Ayurveda clinics are emerging across India tapping even the "medical tourism" concept emerging globally, in Kerala state, the so called "God's own country" [69] or in cities such as Pune [70] or aforesaid Jain clinic at Indore city [11] .
These usually run to the full capacity and/or are overbooked with few weeks/ months of waiting.Hence, some enterprises like aforesaid Jiva provide telemedicine consultation and courier the drugs.Another "Huma" therapy at Lucknow city is acompletely Ayurvedic clinic for cancer using herbal mixture comprising Azadirachta indica A. Juss., Curcuma longa L., Emblica officinalis gaertn., Ocimum sanctum L., Semecarpus anacardium L., Tinospora cordifolia [Willd.]Miers. [71]Most of these clinics employ Ayurvedic detox therapy named as "Panchkarma" [5 actions-Vamana [vomiting], Virechana [purgation], Niruham [decoction enema], Anuvaasan [oil enema], and Nasyam [nasal administration]. [72][73]An Ayurvedic tonic named "Chayavanprash" with "aforesaid Triphala" as the main drug and many other herbs is popular too for disease prevention and immunity building, especially since COVID-19 pandemic. [38][39]ientists have repurposed to treat cervical cancer "Panchvalkal", an Ayurvedic traditional formulation has references in Charak Samhita and Bhavaprakasha Nighantu used for the treatment of women with endometriosis-related problems, leucorrhea and vaginal ailments [74] .The formulation comprises the barks of trees Ficus glomerata Roxb., Ficus religiosa L., Ficus benghalensis L., Ficus virens Aiton, and Thespesia populnea [L.] Soland ex.Correa.However, the 1 st 3 tree species being sacred in India their bark harvest is a taboo. [75]milarly, traditional Chinese medicine [TCM] has developed formula PHY906, decoction of a mixture of the four herbs: Glycyrrhiza uralensis Fisch, Paeonia lactiflora Pall, Scutellaria baicalensis Georgi and Ziziphus jujuba Mill, for over 1800 years for treating a variety of gastrointestinal distress such as diarrhoea, cramps, nausea, vomiting etc. [76][77] A concern raised about Ayurvedic drugs was the content of heavy metals considered toxic such as mercury leading to prohibition of import of some Ayurvedic medicines in USA about 2 decades ago.However atomic and biochemical studies found that these "bhasma" when given in higher doses to rats does not get absorbed in the gastrointestinal tract but gets excreted. [78]Further it said that a study on the neurotoxic effect and accumulation of methyl mercury and mercuric sulfide [HgS] in rats indicates that inorganic HgS can be absorbed in the insoluble form in the G-I tract and that its neurotoxic potency is about 1,000 times less than that of the soluble MeHg.Xinc oxide nanoparticles [nZnO] Experiments showed selective toxicity to different bacterial systems and human T lymphocytes.A standardized colloidal gold preparation [Tyndall's purple, Au, 27 nm] is found to be a far more effective anti-arthritic agent in rats than the sodium aurothiomalate used in the treatment of rheumatoid arthritis.Swarna bhasma [42 iterations, 900 C] was prepared brown red in colour following the classic texts.An infrared spectrum showed no presence of organic compounds and transmission electron microscope [TEM] measurements revealed average particle size to be 57 nm with globular morphology.An atomic absorption spectroscopy indicated the bhasma to be free of any mercury but having 92% zerovalent gold [Au] in the bhasma.These nanogold particles should be able to reach the affected site even if administered orally and provide a slow and sustained release of Au [I] ions.he southern Indian traditional medicine branch called "Siddha" that developed mainly in the Tamil nadu state was supposedly most expert in employing heavy metals in highly processed, no-toxic forms such use of vermillion, a lead compound [Pb 3 O 4 ] for treating hepatitis C virus [HCV] and found ot be non toxic to humans. [82]Another in vitro study showed that Rasagenthi Mezhugu [RGM], a popular Siddha medicine containing toxic metals such as mercury, lead, and arsenic is useful to cure cervical cancer cells and not toxic to the healthy cells. [83]ani is another traditional medicine system in India that also has similar herbal and/ or metallic medicines found to be effective for millennia and found to be useful in treating even cervical cancer. [84]Other studies have also shown the anticancer potential of Islamic medicine. [85]Other traditional medical practices worldwide may also have useful elements to integrate into the modern medicine for better efficacy/ relief to the patient from ADR. [25] Bioactives such as Curcumin, [40] Quercetin [86] and Resveratrol [87] are also now being proposed to address cancer, the latter being at low cost, almost painless by the Premier cancer research institute in India!Further, innovative, natural products based therapies in cancer are being proposed such as using vitamin C [88] and vitamin D [89] .Chemotherapy is likely to produce de novo antimicrobial resistance [AMR] in gut microbiota by activating the bacterial SOS system. [90][91]Chemotherapy is damaging to the commensal gut microbiota and changes in gut microbiota are significant precursors to sepsis in cancer patients.Microbiome-based therapeutic interventions may be able to correct dysbiosis and prevent carriage of antimicrobial-resistant pathogens.The global spread of antibiotic-resistant pathogens threatens to increase the mortality of cancer patients significantly.We propose that chemotherapy contributes to the emergence of antibiotic-resistant bacteria within the gut and, in combination with antibiotics, drives pathogen overgrowth and translocation into the bloodstream.In our model, these processes are mediated by the effects of chemotherapy on bacterial mutagenesis and horizontal gene transfer, the disruption of commensal gut microbiology, and alterations to host physiology.Herbal medications may be helpful in addressing AMR issues their use in cancer treatment is worth exploring urgently, including in veterinary care given the rising importance of zoonotic diseases as COVID-19 showed. [92]Bioactive from common crop plants such as spices such as Coriander can alleviate the ecological risk of species extinction due to overharvest as proposed in the case of Asoca tree {Saraca asoca [Roxb.]De Wilde} used to treat menorrhagia in Ayurveda across south-east Asia contribute to environmental sustainability. [93]The study also quotes its utility in cancer therapy.Of course, cultivation as pesticide free, with organic inputs is a prerequisite to minimize the cancer risk.

Global and public health outlook
Tobacco use, alcohol consumption, unhealthy diet, physical inactivity, air pollution and microbial infections are identified as major causes behind cancer [1] and these need to be addressed on priority basis.Cancer burden puts unequal burden in poorer countries as evident from the fact that In developed countries, 8% women are diagnosed with breast cancer and 1 in 71 women die of it say WHO. [2]By contrast, in less developed countries; only 4% women is diagnosed with breast cancer, 1 in 48 [2%] women die from it.In the less developed countries, there were 543,337 deaths & 811,014 new cancer patients the ration being 70% in 2018 while in the highly developed countries of there were 9,296,171 new cancer cases and 3,643,502 cancer deaths, at 40%.WHO estimates that the number of new cancer cases in 2050 will rise 77% to a total of 35 million cases. [94]WHO further estimates that in 2050, the mortality amounts in the low and medium human development index countries may almost double.WHO referenced survey data from 115 countries on components of their universal health coverage, only 39% of these countries included basic cancer management as part of health benefit packages [HBP] for their citizens!The less developed countries with lower healthcare budget can benefit from the herbal medicines.The traditional medicine policy of WHO is a step in that direction. [95]atements and Declarations Qeios, CC-BY 4.0 • Article, March 27, 2024 Qeios ID: 95EWHI • https://doi.org/10.32388/95EWHI1/18 Qeios, CC-BY 4.0 • Article, March 27, 2024 Qeios ID: 95EWHI • https://doi.org/10.32388/95EWHI2/18 traditional medicinal system in India for millennia, in the context of modern science.The purpose of this article, a mini review, is to: a. Enlist top priority ayurvedic herbs & their bioactive ingredients in treating cancer, b.Mention briefly the pharmacological action of these herbs/ their ingredients in modulating cancer physiology, c.Highlight literature evidence regarding efficacy and safety of these herbs briefly.
increase in telomerase activity with no change in telomere length in peripheral blood mononuclear cells[8](a)

Table 1 .
Main cancer types prevalence & mortality in

Table 3 .
Common Ayurvedic herbs/ bioinputs with bioactive ingredients and mechanism of action of the 706 cancer survivors.Most of the participants [83%] suffered from the effects of cancer treatment; both late and long-term.Commonest effects were fatigue [59%], sleep disorder [41%], hot flashes [39%], nerve damage [polyneuropathy, 38%], and pain [36%] with a mean number of 5.1 of different effects.Nearly half of the such participants complaining late and long-term effects [43%] reported using CAM for redressal.Self-help practices [26%] were commonest such as relaxation therapy [19%], yoga [14%] and meditation [13%], but 22% also visited to CAM providers.Herbal-and other natural remedies were used by 13% for redressal.Majority of the CAM users reported self-perceived improvements of their symptoms [86% for self-help practices, 90% for visits to CAM providers].Few (<10%) experienced adverse effects of the CAM treatment.
A healthy and balanced diet is important for overall wellness.This includes: eating a plant-based diet and have at least 5-9 servings of fruit and vegetables daily including beans in your diet eating whole grains [such as cereals, breads, and pasta] several times daily choosing foods low in fat and low in salt" Green tea, Cannabis, Black cohosh, Turmeric, Giinger, Echinacea, St John's wort, milk thistle] to compare ADRs described in ICSRs with the literature.A total of 1057 ICSRs were extracted from the database but only 134 were adequate [or did not concern too many therapeutic lines] so analysed, of which, 51 rationalizable ICSRs could be explained, leading to a pharmacokinetic or pharmacodynamic interaction mechanism.Reports concerned more frequently women and half of the admissible ICSRs involved Viscum album and Silybum marianum.