FROM CONVENTIONAL TO COMPLEMENTARY: PHYTOTHERAPY IN LUNG CANCER MANAGEMENT

FROM CONVENTIONAL TO COMPLEMENTARY: PHYTOTHERAPY IN LUNG CANCER MANAGEMENT

Pushpendra Kumar, Umakant Sahu, Harkesh Dadsena, Chhavi Rahangdale, Lokprabha Hirwani, Bhoomika Swarnkar, Abhishek Nand, Helina Tondan, Yashika Israni and Vishal Jain *

Department of Pharmacognosy, University Institute of Pharmacy, Pt. Ravishankar Shuka University, Raipur, Chhattisgarh, India.

ABSTRACT: Lung cancer, which is primarily caused by smoking tobacco products, environmental pollutants, and genetic predispositions, continues to be ranked among the biggest contributors of cancer-related death worldwide. Numerous sophisticated cancer treatment methods are inefficient because of metastatic spread and susceptibility to traditional anti-cancer medications. Natural therapeutic compounds developed from plants are presently of considerable curiosity because of their excellent absorption and lack of side effects. Relevant instances involve ginsenosides (from ginseng), curcumin (from Curcuma longa), resveratrol (from grapes), and epigallocatechin gallate (from green tea). These compounds all alter important molecular pathways linked to the growth of lung cancer including NF-κB, STAT3, MAPK, and PI3K/Akt signalling. This article highlights the molecular understandings, experimental evidence, and fresh clinical data that support the utilization of natural products effective adjuvant and chemo preventive therapy for lung cancer.

Keywords: Lung cancer, Herbal medicine, Adjuvant treatments, Mortality, Phytotherapy

INTRODUCTION: One of the most difficult problems in oncology is still lung cancer ¹. Due to tobacco use and air pollution, lung cancer is one of the highest rates of mortality worldwide. It is a disease marked by excessive growth of cells ². About 85% of occurrences of lung cancer are caused by tobacco use, making it the primary cause of the disease ³. Nicotine exposure contains carcinogens including nitrogenous compounds and PATH that directly harm DNA and cause errors in important genes like TP53, KRAS, and EGFR ⁴. However, lung cancer also occurs in non-smokers, underscoring the role of other environmental and occupational exposures ⁵. Long-term exposure to air pollutants such as nitrogen oxides, particulate matter (PM2.5), and volatile organic compounds greatly raises the risk ⁶.

Lung cancer is mostly caused by radioactive decay products, such as radon gas, which can build up inside ⁷. Additional risk factors include exposure to asbestos, arsenic, and silica dust, as well as chronic lung inflammation and genetic susceptibility ⁸. Together, these environmental and lifestyle factors contribute to the complex etiology and rising burden of lung cancer globally ⁹. Since it is hard to restrict the development of the tumor in its intermediate and terminal stages, the purpose of curative therapy for lung cancer is to ensure mortality ¹⁰. When cancer is treated chemically, there are frequently severe adverse reactions, medication obstruction, and substandard clinical results ¹¹.

Consequently, there is an urgent need for effective preventive and adjunctive strategies that can not only inhibit tumor development but also protect normal lung tissue and improve therapeutic outcomes ¹². Many cultures have relied on traditional herbal remedies for centuries to manage respiratory illnesses, reduce inflammation, and strengthen immunity.

These phytochemicals can scavenge reactive oxygen species, modulate detoxification enzymes, inhibit oncogenic signalling pathways, and enhance the body’s immune defences against tumor cells ¹³. Numerous herbal remedies have demonstrated notable anti-tumor effects on immunological regulation ¹⁴. For example, it has been demonstrated that the compounds curcumin from turmeric (Curcuma longa), resveratrol from grapes, and epigallocatechin gallate from green tea inhibit the formation of lung tumors via controlling pathways related to blood vessel formation, cell death, cell division, and transmission ¹⁵. Similarly, ginsenosides from ginseng have shown encouraging results in the cancerous preliminary studies ¹⁶.

Lung Cancer Prevalence and Patterns: One of the most dangerous public health problems in the world, lung cancer still has a major impact on incidence, mortality, and prevalence in both developed and developing nations, including those in Asia, Europe, North America, Latin America and the Caribbean, Africa, and Oceania ¹⁷. It now accounts for 12.4% of all cancer cases and has surpassed breast carcinoma as the most prevalent form of cancer incidence globally, with an anticipated 24,80,675 new cases in 2022. The lung cancer incidence, mortality and prevalence in Asia (63.1%, 62.9%, 63.9%), Europe (19.5%, 20.7%, 18.9%), Northern America (10.4%. 8.3%, 10.1%), Latin America and the Caribbean (4.2%, 5.0%, 4.2%), Africa (2.0%, 2.5%, 2.2%), Oceania (0.71%, 0.69%, 0.66%) according to IARC Fig. 1 & 2. Lung cancer incidence is notably high in Asia due to a combination of factors, primarily including high rates of tobacco use, exposure to air pollution, and genetic predispositions. According to epidemiologic research conducted in East Asia, including the republics of China, Japan, Mongolia, North Korea, and the Republic of Korea, almost thirty percent of all lung cancer individuals never smoked ¹⁸.

FIG. 1: WORLD HEALTH ORGANIZATION: ESTIMATED NUMBER OF LUNG CANCER CASES IN 2022, WORLDWIDE

FIG. 2: NUMBER OF NEW CASES, BOTH SEXES, ALL AGES

Pathophysiology of Lung Cancer: Lung cancer comes in two main forms: SCLC and NSCLC. Approximately 10% to 15% of all lung cancers are SCLC, while 80% to 85% of lung cancers are NSCLC. Around 80% to 85% of lung cancer cases globally are NSCLC rather than SCLC ^{19, 20}.

Complex genetic and molecular changes that promote unchecked cell proliferation are part of the pathology underlying NSCLC ²¹. Genes like EGFR, KRAS, and ALK frequently have important mutations that activate signaling channels like PI3K/AKT and MAPK, which support tumor cell proliferation, survival, and inhibition of death. Additionally, tumor suppressor genes like TP53 may be inactivated, further enabling malignancy ²². NSCLC can also exploit the immune system by overexpressing PD-L1, allowing them to evade immune detection ²³. VEGF promotes blood vessel development, which keeps the growth of tumors going by providing a steady flow of oxygen as well as nutrients ²⁴. These molecular insights have paved the way for targeted therapies and immunotherapies, improving patient outcomes. However, resistance mechanisms and tumor heterogeneity remain major challenges in effective NSCLC management ²⁵.

The forceful neuroendocrine system carcinoma known as small cell lung cancer (SCLC) is distinguished by its quick growth and early metastases ²⁶. The disease mostly affects the central airways and is closely associated with tobacco use, which results in mutations in DNA such the deactivation of the genes that regulate tumor suppression RB1 and TP53 ²⁷. Loss of TP53 disrupts the cell’s ability to repair DNA damage and regulate apoptosis, while RB1 loss removes control over cell cycle progression, driving uncontrolled proliferation ²⁸. Amplification of MYC family oncogenes further accelerates tumor growth and promotes metabolic reprogramming ²⁹. Neuroendocrine markers, including synaptophysin and chromogranin A, are commonly expressed, reflecting the tumor’s origin from neuroendocrine precursor cells ³⁰. SCLC cells secrete paracrine factors that create an immunosuppressive microenvironment and enhance angiogenesis, supporting tumor expansion and dissemination ³¹. Due to its high mitotic index and propensity for early spread to the brain, liver, and bone marrow, SCLC often presents at advanced stages, making treatment challenging ³² Fig. 3.

FIG. 3: PATHOPHYSIOLOGY OF LUNG CANCER

Treatment and their Problems: Highly effective approaches for combating lung cancer are treatments called immunotherapies that involve ³³.

Cytokines and other Non-specific Immunotherapies: Cytokines are proteins that help immune cells communicate, and some are being tested to treat lung cancer ³⁴. MABP1 blocks IL-1α, a protein linked to cancer growth. In a small study, lung cancer patients pretreated with EGFR-targeting drugs lived longer with MABP1. IL-2, another cytokine, showed mixed results one large study found no benefit, while a smaller study combining IL-2 with chemotherapy and surgery improved 5-year survival. IL-15, given under the skin, boosted natural killer cells that fight cancer. An IL-15-based drug, ALT-803, combined with nivolumab, helped patients whose cancers resisted other treatments ^{35, 36}.

Problems: Cytokines and other non-specific immune-mediated therapies seek to strengthen the body's resistance generally against cancer; however, they frequently result in major issues ³⁷. Widespread immunological activation brought on by treatments utilizing cytokines like IL-2 and IL-15 can result in serious adverse effects such fever, low blood pressure, exhaustion, and organ damage ³⁸. While some studies show improved survival, results are inconsistent and benefits are limited to select patients ³⁹. High toxicity often restricts dosing and long-term use. Additionally, cytokines can unintentionally promote inflammation that harms healthy tissues. Overall, while promising, non-specific cytokine therapies require careful monitoring and more research to improve safety and effectiveness in lung cancer ^{40, 41}.

Monoclonal Antibodies (mAbs) and Immune Checkpoint Inhibitors: Monoclonal antibodies (mAbs) are proteins that bind to targets on cancer cells to block growth signals or mark them for immune destruction ⁴². ICIs block proteins like PD-1, PD-L1, and CTLA-4, helping the immune system attack cancer ⁴³. Approved ICIs for lung cancer include pembrolizumab, nivolumab, atezolizumab, and durvalumab ⁴⁴. ADCs, like trastuzumab deruxtecan for HER2-positive lung cancer, deliver chemotherapy directly to tumors. There are also other ADCs in development that target HER2, HER3, Trop-2, and c-Met ⁴⁵.

Problems: Immune checkpoint inhibitors (ICIs) and monoclonal antibodies (mAbs) have increased lung cancer survival by reviving immune responses and obstructing cancer growth signals ⁴⁶. However, they can cause serious side effects. ICIs often trigger immune-related problems, like inflammation of the lungs, liver, intestines, or skin. Some patients develop severe pneumonitis or colitis requiring steroids or stopping treatment ⁴⁷. mAbs may lead to infusion reactions, fatigue, and risk of infections. Combination therapies, though more effective, increase toxicity ⁴⁸. Additionally, not all patients respond, especially those without specific targets or biomarkers, making it essential to identify who will benefit from these treatments safely ⁴⁹.

Oncolytic Virus Therapy: Oncolytic virus research for lung cancer is presently being conducted in 14 clinical research studies ⁵⁰. Oncolytic viruses are special viruses designed to mainly infect and destroy cancer cells ⁵¹. As they multiply inside the tumor, they kill cancer cells directly and also trigger the immune system to attack the tumor ⁵². In one early study (Phase 1), a virus called enadenotucirev (formerly ColoAd1), which targets tumors, was given through a vein to lung cancer patients before their tumors were removed ⁵³. This treatment caused a strong local immune response and brought many cancer-fighting CD8+ T cells into the tumor ⁵⁴. Another approach uses vaccines made from tumor cells infected with modified adenovirus or vaccinia virus (called VIReST) to help train the immune system ⁵⁵.

This method could prevent tumors from growing in high-risk people and create lasting protection against cancer ⁵⁶. The myxoma virus (MYXV) is a poxvirus that normally only infects rabbits and doesn’t cause disease in other animals ⁵⁷. Surprisingly, MYXV can infect and kill human cancer cells from different tumor types. Researchers tested MYXV in lab models of small-cell lung cancer (SCLC) to see if it could be used as a treatment ⁵⁸. An oncolytic therapeutic vaccination teaches the immune response to identify and combat cancer cells more successfully by combining an oncolytic virus with antigens linked to cancer ⁵⁹.

Problems: Using viral designed to spread and eliminate cancerous cells while triggering immune responses, oncolytic virus treatment ⁶⁰. Treatments like enadenotucirev and myxoma virus show promise in lung cancer by attracting immune cells to tumors and killing cancer cells directly ⁶¹. However, this therapy has challenges. Some patients may develop fever, inflammation, or flu-like symptoms ⁶². Delivering the virus effectively to all tumor sites can be difficult, and the body’s immune system may clear the virus before it works ⁶³. There is also a risk of harming healthy tissues or causing unexpected infections. More research is needed to improve safety and effectiveness ⁶⁴.

Cancer Vaccines: There are different types of lung cancer vaccines. Some use proteins or small pieces of proteins (like MAGE-A3 or L-BLP25), while others use whole cells (like GVAX or Belagenpumatucel-L) ⁶⁵. For example, the MAGE-A3 vaccine was tested in a large clinical trial for patients whose tumors had the MAGE-A3 protein, which is linked to worse outcomes ⁶⁶. The vaccine used the MAGE-A3 protein mixed with an immune booster ⁶⁷. Sadly, the study showed no benefit patients did not live longer without cancer returning so this vaccine is no longer being developed for lung cancer ⁶⁸.

Another vaccine, TG4010, targets a protein called MUC1 and uses a harmless virus (MVA) to deliver MUC1 and an immune-boosting signal (IL-2) to the body. Belagenpumatucel-L is made from lung cancer cells that have been treated so they can’t grow. It contains genetic material to block TGF-β, substance cancers use to weaken the immune system ^{69, 70}.

Problems: The MAGE-A3 vaccine failed to show any improvement in how long patients lived without cancer coming back, even in those whose tumors had the MAGE-A3 protein, leading to the end of its development for lung cancer ⁷¹. Belagenpumatucel-L also faced problems because lung cancers use many ways to hide from the immune system, like reducing important immune recognition proteins or releasing substances that suppress immune responses ⁷¹. These tactics limit the vaccine’s effectiveness. Overall, both vaccines struggled because the immune system could not generate a strong, lasting attack against the tumor, and the cancer continued to evade detection ⁷².

Anti-Lung Cancer Activities of Plants as A Potential Herbal Medicine:

Panax ginseng: Ginseng (Panax ginseng) has garnered a lot of interest as a potential natural remedy and preventative measure for lung cancer because of its many bioactive components, chiefly ginsenosides ⁷³. Recent studies have elucidated that ginsenosides exert anticancer effects through multiple molecular mechanisms ⁷⁴. By causing cell cycle arrest at the G0/G1 or G2/M phases, they prevent the growth of lung cancer cells. This is accomplished by upregulating the proteins p21 and p27 and downregulating cyclin-dependent kinases ⁷⁵. It has been demonstrated that ginsenosides like Rg3 and Rh2 cause apoptosis through mitochondrial pathways, which are marked by a boost in the Bax/Bcl-2 ratio, cytochrome c release, and caspase-3 initiation ⁷⁶. Additionally, ginseng inhibits the PI3K/Akt and NF-κB signaling pathways, which lowers the expression of VEGF, also known as vascular endothelial growth and collagen metalloproteinases (MMP-2 and MMP-9). This decreases angiogenesis and metastasis ⁷⁷. Emerging evidence also indicates that ginseng modulates the tumor microenvironment by enhancing immune surveillance, reducing chronic inflammation, and regulating oxidative stress through activation of Nrf2-dependent antioxidant enzymes ⁷⁸. Notably, nanoparticle formulations of ginsenosides have improved their bioavailability and demonstrated enhanced anticancer efficacy in lung tumor xenograft models ⁷⁹. Collectively, these mechanistic insights underscore the potential of ginseng as both a chemopreventive and therapeutic agent against lung cancer, warranting further clinical investigation ⁸⁰.

TABLE 1: LIST OF HERBAL PLANT THAT’S HAVE ANTI LUNG CANCER ACTIVITY

Althaea officinalis: The marshmallow, Althaea officinalis L., has long been used to treat respiratory conditions because of its calming, anti-inflammatory, and mucilaginous qualities ⁹¹. Recent pharmacological investigations have highlighted its potential in lung cancer prevention and therapy ⁹². The plant's bioactive constituents particularly flavonoids (e.g., quercetin, kaempferol), phenolic acids, and polysaccharides exert anticancer effects through multiple mechanisms ⁹³. Studies suggest that extracts of A. officinalis can inhibit lung cancer cell proliferation by inducing cell cycle arrest and promoting apoptosis via mitochondrial-dependent pathways, characterized by activation of caspase-3 and enhanced Bax/Bcl-2 ratio ⁹⁴. Additionally, by increasing levels of enzyme and superoxide dismutase (SOD) and decreasing intracellular reactive oxygen species (ROS), A. officinalis demonstrates strong antioxidant activity, shielding pulmonary cells against oxidative DNA damage, a major cause of cancer ⁹⁵. Suppression of NF-κB signaling, which is essential for tumor development and metastasis, and decreased levels of pro-inflammatory cytokines like IL-6 and TNF-α have also been shown to have anti-inflammatory properties⁹⁶. In experimental lung models, A. officinalis extract reduced histopathological damage, preserved alveolar architecture, and attenuated inflammatory cell infiltration ⁹⁷. These findings suggest that Althaea officinalis may offer dual benefits protecting healthy lung tissue while exerting antiproliferative effects on malignant cells positioning it as a promising adjunct in lung cancer prevention and supportive therapy. However, further in-depth molecular studies and clinical validation are required to fully establish its efficacy and safety in oncology ⁹⁸. (Table 1 provided list of major plants in lung cancer activity).

Achillea millefolium: Recent investigations have identified Achillea millefolium (yarrow) as a promising source of anticancer compounds against lung cancer ⁹⁹. By causing G2/M cell cycle arrest and initiating intrinsic apoptosis via mitochondrial mechanisms, its flavonoids (including apigenin and luteolin), phenolic acids, and sesquiterpene lactones have antiproliferative actions. Those factors stimulate caspase-3 and caspase-9, raise the Bax/Bcl-2 ratio, and encourage cytochrome c release ¹⁰⁰. Furthermore, yarrow extracts reduce inflammatory mediators and lower tumor-promoting cytokines including TNF-α and IL-6 via inhibiting the PI3K/Akt and NF-κB signaling pathways. By neutralizing oxygen pollutants and upregulating Nrf2-regulated enzymes that inhibit free radicals, Achillea millefolium also exhibits antioxidant action, shielding lung epithelial cells from oxidative DNA damage^.101. Recent in-vivo studies have shown reduced tumor growth and improved lung histopathology following yarrow treatment¹⁰². Together, these findings highlight A. millefolium as a multi-targeted natural agent with chemo preventive and therapeutic potential against lung cancer ¹⁰³.

Taraxacum mongolicum: Taraxacum mongolicum, often referred to as Mongolian dandelion, has emerged as a promising medicinal herb with anticancer potential, notably in respiratory malignancies such as lung cancer ¹⁰⁴. Recent studies have identified that its bioactive components including taraxasterol, chlorogenic acid, caffeic acid derivatives, and polysaccharides exert multiple chemopreventive and therapeutic mechanisms ¹⁰⁵. According to in-vitro studies, T. mongolicum extracts dramatically reduce the growth of non-small cell lung cancer cells by downregulating the production of CDK4 and cyclin D1, which causes cell cycle arrest at the G0/G1 phase ¹⁰⁶. Furthermore, as demonstrated by elevated cytochrome c release, caspase-9 and caspase-3 activation, and the Bax/Bcl-2 ratio, taraxasterol stimulates mitochondrial-mediated apoptosis. A key component of its protective impact is its anti-inflammatory action, which is achieved by suppressing the NF-κB and STAT3 signaling pathways. This lowers the production of pro-inflammatory cytokines like TNF-α and IL-6, which are known to promote tumor growth ¹⁰⁷. Furthermore, T. mongolicum exhibits potent antioxidant effects by enhancing the activities of superoxide dismutase and glutathione peroxidase while reducing intracellular reactive oxygen species, thereby protecting lung tissue from oxidative DNA damage and mutagenesis ¹⁰⁸. Recent in-vivo models have confirmed that oral administration of T. mongolicum extract can attenuate tumor growth, inhibit angiogenesis by downregulating VEGF expression, and improve histopathological features of lung tissue exposed to carcinogens ¹⁰⁹. According to these results, Taraxacum mongolicum has multi-targeted effects, including antiproliferative, pro-apoptotic, anti-inflammatory, and antioxidant properties, making it a viable natural option for early detection and supportive treatment of lung cancer ¹¹⁰. To determine its safety, ideal dosage, and therapeutic effectiveness in human populations, more clinical research is necessary ¹¹¹.

Curcuma longa: Over the last few years, a great deal of research has been done on the anticancer effects of Curcuma longa, also known as turmeric, especially in relation to lung cancer ¹¹². Recent research has shown that curcumin, its main bioactive ingredient, inhibits the growth and spread of lung tumors through a variety of ways ¹¹³. By suppressing the production of cyclin B1 and CDK1, curcumin stops cell division by stopping a cell cycle in the G2/M phase ¹¹⁴. Through the mitochondrial route, it triggers apoptosis, which is shown by an elevated Bax/Bcl-2 ratio, depolarization of the cell membrane potential of the mitochondria, release of cytochrome c, and the expression of caspase-3 and caspase-9 ¹¹⁵. Curcumin also inhibits the PI3K/Akt/mTOR and NF-κB signaling pathways, which lowers the transcription of pro-inflammatory and anti-apoptotic genes including Bcl-xL, COX-2, and TNF-α all of which are important contributors to lung carcinogenesis ¹¹⁶. Recent evidence has also highlighted its capacity to inhibit EMT, thereby reducing invasion and metastasis by downregulating matrix metalloproteinases (MMP-2 and MMP-9) and suppressing vimentin production ¹¹⁷. Moreover, curcumin exhibits strong antioxidant activity by eliminating unstable oxygen species and upregulating Nrf2-mediated expression of detoxifying enzymes, protecting normal lung epithelial cells from oxidative DNA damage ¹¹⁸. Novel nano-formulations and curcumin-loaded lipid carriers have further improved its bioavailability and demonstrated enhanced chemotherapeutic efficacy in lung cancer xenograft models ¹¹⁹. Although carefully planned research studies are required to confirm its therapeutic usefulness, these results collectively highlight Curcuma longa's potential as a promising natural drug for the chemoprevention and adjuvant therapy of lung cancer¹²⁰.

Allium sativum: Recent research highlights Allium sativum (garlic) as a potent natural agent against lung cancer through multiple mechanisms ¹²¹. Allicin, diallyl disulphide, and S-allyl cysteine are examples of bioactive sulphur compounds that stop the growth of lung cancer cells by causing a cell cycle stoppage and triggering the mitochondrial mortality systems ¹²². These compounds upregulate Bax, downregulate Bcl-2, and trigger caspase-3 activation, promoting programmed cell death ¹²³. Garlic extracts also suppress PI3K/Akt and NF-κB signaling, reducing inflammatory cytokines (TNF-α, IL-6) that support tumor growth ¹²⁴.

Additionally, garlic’s antioxidant properties decrease reactive oxygen species and prevent oxidative DNA damage in lung epithelial cells ¹²⁵. Recent in-vivo studies have demonstrated that garlic supplementation attenuates tumor volume and limits metastasis by inhibiting matrix metalloproteinases and angiogenesis markers like VEGF ¹²⁶. Collectively, these findings indicate that Allium sativum offers multi-targeted protective effects, supporting its role as a chemopreventive and adjunct therapeutic agent against lung cancer ¹²⁷.

Taxus brevifolia: Taxus brevifolia, the Pacific Yew, is renowned for producing paclitaxel, a diterpenoid extensively used in lung cancer chemotherapy ¹²⁸. Paclitaxel possesses curative properties through stabilizing microtubules and preventing their depolymerization, which arrests the cell cycle at the G2/M phase and leads to mitotic catastrophe ¹²⁹. According to recent studies, paclitaxel also causes lung cancer cells to undergo mortality by triggering the release of cytochrome c and activating caspase-9 and caspase-3 ¹³⁰. Furthermore, paclitaxel decreases the formation of vessels by downregulating vascular endothelial growth factor (VEGF) and inhibits epithelial–mesenchymal transition, reducing metastasis potential ¹³¹. Emerging nanoparticle formulations and albumin-bound paclitaxel have enhanced drug solubility, tumor targeting, and reduced systemic toxicity ¹³². Studies also report paclitaxel’s ability to alter antibody responses by encouraging the developmental stages of dendritic cells and enhancing cytotoxic T-cell activity against lung tumors ¹³³. Collectively, Taxus brevifolia remains a cornerstone in lung cancer treatment due to its unique multi-targeted mechanisms and clinical efficacy ¹³⁴.

Tinospora cordifolia: Recent investigations highlight Tinospora cordifolia (Guduchi) as a promising botanical for lung cancer prevention and adjunct therapy ¹³⁵. Its bioactive constituents, including tinosporaside, berberine, and cordifolioside, exert multiple anticancer mechanisms ¹³⁶. Studies demonstrate that T. cordifolia extracts induce apoptosis in lung cancer cells by increasing Bax/Bcl-2 ratios, activating caspase-3, and disrupting mitochondrial membrane potential ¹³⁷. Furthermore, the plant downregulates pro-inflammatory cytokines such as TNF-α and IL-6 by inhibiting NF-κB signaling, thereby reducing tumor-promoting inflammation ¹³⁸. Antioxidant properties further contribute to chemoprevention by eliminating unstable oxygen species and enhancing endogenous defense enzymes like superoxide dismutase and catalase, protecting lung tissue from oxidative DNA damage ¹³⁹. In-vivo models show that T. cordifolia suppresses tumor growth, preserves lung histoarchitecture, and improves immune responses by stimulating natural killer cell activity. Collectively, these findings underscore Tinospora cordifolia’s multi-targeted promise as an organic, safe lung cancer treatment management and prevention ¹⁴⁰.

Vitis vinifera: Vitis vinifera (grape) has gained attention for its rich polyphenolic content, especially resveratrol and proanthocyanidins, which exhibit potent anticancer effects against lung cancer ¹⁴¹. According to recent research, resveratrol causes lung cancer cells to undergo mortality via triggering the breakdown of mitochondria, which is shown by an elevated Bax/Bcl-2 ratio and caspase-3 activation ¹⁴². It also inhibits cell proliferation by arresting the cell cycle at the S-phase and suppressing cyclin D1 expression ¹⁴³. Additionally, resveratrol downregulates PI3K/Akt and NF-κB signaling, reducing pro-inflammatory cytokines and survival signals critical for tumor growth ^{144, 145}. Grape-derived polyphenols exhibit strong antioxidant properties, scavenging reactive oxygen species and protecting lung epithelial cells from oxidative DNA damage ¹⁴⁶. In-vivo models reveal that grape extracts suppress angiogenesis by lowering VEGF levels and inhibit metastasis through modulation of matrix metalloproteinases ¹⁴⁷. Collectively, Vitis vinifera demonstrates multi-targeted chemo preventive and therapeutic potential, supporting its use as a complementary strategy against lung cancer ¹⁴⁸.

Camellia sinensis: Camellia sinensis, widely consumed as green tea, has shown significant anticancer potential against lung cancer through its abundant polyphenols, particularly EGCG ¹⁴⁹. According to recent research, EGCG suppresses the growth of lung cancer cells by downregulating cyclin D1 and CDK4 to cause cell cycle arrest at the G1 phase ¹⁵⁰. Through mitochondrial mechanisms, it induces apoptosis, which is shown by an increase in the Bax/Bcl-2 ratio, cytochrome c release, and caspase-3 activation. Furthermore, EGCG inhibits the MAPK and PI3K/Akt signalling mechanisms, which lowers tumor growth and survival. Because of its potent antioxidant properties, it scavenges reactive oxygen species and shields cells in the lung epithelium from DNA oxidation ¹⁵¹. Green tea polyphenols also inhibit angiogenesis by downregulating VEGF and limit metastasis by decreasing matrix metalloproteinase expression ¹⁵². Recent in-vivo studies confirm that green tea extracts reduce tumor volume and improve survival in lung cancer models ¹⁵³. Collectively, Camellia sinensis offers promising chemo preventive and therapeutic benefits for lung cancer management ¹⁵⁴. (Table 2 & Fig. 4 provided major phytoconstituents in lung cancer activity)

TABLE 2: LIST OF PLANT BASED INDIVIDUAL COMPOUNDS SHOWING ANTI LUNG CANCER ACTIVITY

FIG. 4: POTENTIAL HERBAL COMPOUNDS THAT’S HAVE INHIBITORY ACTION IN LUNG CANCER

TABLE 3: LIST OF ANOTHER HERBAL PLANT THAT’S HAVE ANTI LUNG CANCER ACTIVITY

CONCLUSION: In conclusion, comparison to different cancers, lung cancer is becoming more common and fatal globally. This is mostly because of genetic predispositions, environmental contaminants, and tobacco smoking. Despite being frequently used, significant side effects, limited efficacy in advanced stages, and the evolution of drug resistance are some of the challenges faced by conventional chemotherapy. The necessity to investigate methods that can improve treatment results while lowering toxicity is highlighted by this. One possible interdisciplinary strategy for the treatment of lung cancer is phytotherapy, which uses bioactive compounds produced by plants. While typically having fewer side effects than traditional medications, natural substances like ginsenosides, curcumin, resveratrol, and epigallocatechin gallate have shown the capacity to modify important molecular pathways, such as NF-κB, STAT3, MAPK, and PI3K/Akt, which are crucial for the development, progression, and metastasis of tumors. In the future, lung cancer care may undergo a significant shift with the adoption of an integrated treatment strategy which integrates the benefits of contemporary chemotherapy with based on research phytotherapy, eventually providing patients with better outcomes of life and better life chances.

ACKNOWLEDGEMENT: Nil

CONFLICT OF INTEREST: Nil

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     How to cite this article:

     Kumar P, Sahu U, Dadsena H, Rahangdale C, Hirwani L, Swarnkar B, Nand A, Tondan H, Israni Y and Jain V: From conventional to complementary: phytotherapy in lung cancer management. Int J Pharmacognosy 2026; 13(6): 512-28. doi link: http://dx.doi.org/10.13040/IJPSR.0975-8232.IJP.13(6).512-28.

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