Review on medicinal plants of Sikkim Himalayan region with emphasis on anticancer study

Plants are still not only important in health care, but they are also the finest and safest hope for future medicine. These local ethnomedicinal plants discovered in Sikkim have been scientifically studied, and the results have been widely disseminated so that people can learn more about effective drug treatments and improve their health. The focus of the prevailing study was to find maximum local ethnomedicinal plants that are found in Sikkim Himalayan region with anticancer study. Published data in this review were all gathered from the online bibliographical databases: PubMed, Science direct, Google Scholar, Research gate, Cochrane, Core, and 1 Library. With the extensive literature review data, it was revealed that 77 medicinal plants found in the Sikkim Himalayan region have proven anticancer activity summarized in Table 1 by considering their local name (Nepali), part used for the treatment procedure, active extracts/study models (both in-vitro and in-vitro ) and cell culture assay (diverse cell lines studies). Out of 77 selected ethno-medicinal plants, 27 plants were active in the in-vivo model remaining 50 plants were active in the in-vitro model. As per the activity found in the active extracts, activity was highest in alcohol (methanol and ethanol extracts), followed by aqueous and ethyl acetate, chloroform, etc. Further research can be conducted on those plants that have shown the most promising anti-cancer efficacy in previous clinical tests, perhaps leading to low-cost plant-derived drugs to combat the expanding cancer epidemic.


INTRODUCTION
Mutations that are inherited, generated by environmental factors, or occur from DNA replication errors cause cancer.In multi-cellular animal creatures, including humans, aging is the most important risk factor for carcinogenesis.Cancer is the first or second leading cause of death in 91 of the 172 nations studied, and third or fourth in another 22 [1].In 2040, an estimated 28.4 million new cancer cases (including non-melanoma skin cancer, except basal cell carcinoma) are expected to be diagnosed worldwide, up to 47% from the 19.3 million cases diagnosed in 2020, assuming national rates remain constant [2].In both urban and rural India, cancer is the second and fourth major cause of adult deaths, respectively.Cancer is currently the leading explanation for ruinous health payment, distress funding, and increasing expenditure before death in every country of the world [3].From 1990 to 2016, India's cancer death rate more than doubled.India's cancer incidence was estimated to be 1.15 million new patients in 2018, and by 2040, it is expected to nearly triple due to demographic changes alone [4].The northeast region of India has the highest cancer incidence rate [six population based cancer registries (PBCRs) for males and four PBCRs for females] compared to other parts of the country.The nasopharynx, hypopharynx, esophagus, stomach, liver, gallbladder, larynx, lung, breast, and cervix uteri were the most common cancer sites in northeast India.As seen by the low 5-year survival rates of breast, cervical, and head and neck cancer in the northeast compared to the rest of India, the region lacks the necessary infrastructure in terms of specialized treatment facilities and human resources.A significant number of cancer patients disorders and diseases [8].Sikkim extends between 270 4′46ʺ to 280 7′48ʺ N and 880 58′00ʺ to 880 55′25ʺ E containing 4,000 flowering species [9].The extraordinary geographical position and wide range of topography, high fertile soil, sufficient rainfall, and presence of a large number of perennial streams make the state of Sikkim one of the treasure houses of biodiversity in the country.Sikkim boasts an abundance of medicinal herbs and traditional medicine.About 550 medicinal plants are used by locals in the Sikkim Himalayas region for various ailments, of which only a few are commercially exploited.Plants are still not only important in health care, but they are also the finest and safest hope for future medicine.These local ethnomedicinal plants discovered in Sikkim have been scientifically studied, and the results have been widely disseminated so that people can learn more about effective drug treatments and improve their health.from the northeast travel beyond the region for treatment and care [5].A lot of work has gone towards reducing the detrimental side effects of medications during cancer treatment, such as limiting side effects on adjacent cells and tissues, improving drug accumulation and efficacy in the lesion, and developing novel drug delivery and targeting systems [6].Medicinal plants are a gift from nature to humanity, assisting them in their quest for improved health.Plants and their bioactive substances have been used in traditional medicine since the dawn of humanity.Phyto chemicals found in some medicinal plant species suppress the progression and development of cancer [7].According to studies, the plant kingdom contains over 250,000 plant species, of which only about 10% have been explored for the treatment of various diseases and approximately 60%-80% of the world's population still relies on traditional remedies for the treatment of common

In vivo
In vitro

In vitro
In vivo

Trabectedin
Ecteinascidia turbinate Sarcoma or ovarian cancer [149,150] and cell viability were used to evaluate the anticancer effects of curcumin on human breast cancer cell lines (MCF-7) [158].HeLa and AGS cell lines were examined with the Artemisia annua extracts.In comparison to leaf extracts, stem extracts had less effectiveness inhibiting cell proliferation.At a dosage of 500 mg/ ml, the ethanolic extract of leaves causes growth inhibitions in HeLa and AGS cells (57.24% and 67.07%), respectively [159].
In terms of toxicity studies, many plants showed some extent of toxicity, Albizia coriaria (Welw.ex) Oliver is used to treat skin conditions, jaundice, cough, sore eyes, postpartum hemorrhage, menorrhagia, threatening abortion, and venereal illnessessyphilis, HIV, and gonorrhea [160].Catharanthus roseus L. is an example, as it contains alkaloids that are neurotoxic, particularly VCS [161].Highly toxic antimitotics-VCS and VBS prevent mitosis in metaphase after attaching to microtubules [162].It is obvious that adverse symptoms such myelosuppression, alopecia, abdominal pains, constipation, nausea, paralytic ileus, mouth ulcers, hepatocellular damage, kidney impairment, pulmonary fibrosis, urine retention, amenorrhea, azoospermia, orthostatic hypotension, and hypertension might occur.These plants have been documented for the commercial medications made from this plant, VCS and VBS.In essence, meticulous monitoring of these medications' administration is required to minimise their negative effects [163][164][165][166]. From one study, luteolin obtained from Daucus carota, Salvia rosmarinus, shielded breast cancer cells from doxorubicin-induced toxicity by decreasing reactive oxygen species production [167].Colchicine was previously considered as a cancer treatment, but it has a few disadvantages: it is highly toxic and exhibits little tumor cell specificity, which causes it to target normal cells.Colchicine hence has a limited role in treating cancer [168].Cucurbitacins I and D undergo acetylation, which increases their hydrophobicity and cytotoxicity, to produce cucurbitacins E and B. In addition to reducing tumor size and weight, cucurbitacin E and doxorubicin are effectively cytotoxic for tumor cells in culture and in vivo [169][170][171].A once-daily intraperitoneal injection of 1,100 mg/kg of Withania somnifera extract did not cause any death within 24 hours in Swiss albino mice.However, an acute toxicity investigation found that a small dose increase results in death, with an LD50 of 1,260 mg/kg/body weight.The components of peripheral blood did not alter.But the weights of the spleen, thymus, and adrenal glands were significantly decreased [172].Artemia salina larvae were poisonous to the ethanolic leaf extract of Hyptis capitata Jacq., with the greatest toxicity value being 196,772.7 g/ml [173].

DISCUSSION
In drug development and therapy, particularly cancer research, plants and their secondary metabolites play a significant role.The goal of this review article is to list out the medicinal plants, their extracts, and metabolites that have recently attracted attention for their anticancer effects in vitro and in vivo from Sikkim Himalaya.Although the actual compounds isolated from the plant are frequently not used as medications, they provide clues for the creation of prospective novel agents [151].Plants have been a major source of extremely successful conventional drugs for the treatment of many types of cancer [152].Some of the drugs that failed earlier clinical tests are now igniting renewed interest as new technologies are created.The potential for attaching medications to carrier molecules targeted at certain cancers is demonstrated [153].Natural products might be an important source of antitumor drugs for contemporary cancer treatment.It is anticipated that new anticancer phytopharmaceuticals made from medicinal plants will be useful for both cancer therapy and prevention [154].The plant extracts having rich flavonoids have shown a chemopreventive role in cancer through their effects on signal transduction in cell proliferation and angiogenesis [155].Some of the potential marketed plant-based drugs are highlighted in Table 2.As shown in Table 2, certain cancerous targets, such as ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, and pancreatic cancer, are targeted by Paclitaxel (PTX) obtained from Taxus brevifolia Nutt., Vinblastine (VBS), and Vincristine (VCS) obtained from Vinca rosea Linn.used for breast cancer, testicular cancer, neuroblastoma, Hodgkin's and non-Hodgkins lymphoma, mycosis fungoides, histiocytosis and Kaposi's sarcoma, leukemia, malignant lymphoma, Hodgkin's disease, acute erythraemia, and acute panmyelosis.Certain cancer like testicular, breast, pancreatic, lung, stomach, and ovarian cancers are treated by Podophyllotoxin (PTOX) obtained from Podophyllum spp.Camtothecin (CPT) obtained from Camptotheca acuminate is used for molecular targets such as nuclear enzyme DNA topoisomerase type I inhibitor.Eucalyptin A obtained from Eucalyptus globulus, Parthenolide (PN) obtained from Tanacetus parthenium, and Trabectedin obtained from Ecteinascidia turbinate have shown the potential for breast, ovary, prostate, bladder, skin, and oral cavity, thyroid cancer cells, and sarcoma or ovarian cancer.Most of the plant extracts were observed to have growth inhibition effects in the particular cell line, whereas other plant extracts inhibit DNA synthesis.The extract of Morus alba leaves, which includes several phenolic compounds in various solvents, inhibited the proliferation of the HepG2 cell line by stopping the cell cycle in the G2/M phase.This was accomplished by expressing the protein p27Kip1, activating caspases to cause cell death, and inhibiting topoisomerase II activity [156].To investigate the impact of curcumin on the expression of COX-2, human HT-29 colon cancer cells were treated with various amounts of curcumin derived from Curcuma longa.Curcumin reduced the proliferation of HT-29 cells in a concentration-and time-dependent manner.Although COX-2's mRNA and protein expression were inhibited by curcumin, COX-1 was not similarly altered [157].In addition, lactate dehydrogenase and 3-(4,5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide tests to measure cytotoxicity

.
Plants found in Sikkim Himalayan region with reported anticancer activity.

Table 2 .
Plant based anti-cancer marketed drugs.