Review

Promising leads against lung cancer from the plants in Lamiaceae family

Abstract

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Introduction:

Ceaselessly, management of cancer has been the major global challenge for healthcare professionals. As regards, lung cancer (LC) has been introduced as the second most common form of cancer in both men and women, taking the lives of more than a million people each year, statistically holding the highest mortality rate among all cancer types. Although much effort has been made for the management of LC, current therapies are quite ineffective. With reference to the fact that the most current chemotherapeutic agents for LC are of plant origin, the authors hereby collected the acclaimed plants from the Lamiaceae family which have shown remarkable activity against LC.

Methods:

The incorporated papers were published between the years of 1997 and 2023. The principal search keywords for this review article were "lung cancer", "Lamiaceae", "cytotoxic effect", "anti-tumor" and "anti-proliferative" in Medline, Springer, Scopus, ScienceDirect and Google Scholar databases.

Results:

To the furthest extent, different responsible mechanism(s) of action for the anti-cancer properties of each plant are discussed. The respected IC₅₀ values for plant extracts, essential oils or pure isolated compounds are underlined as well.

Conclusion:

Many plants and isolated relative phytochemicals have shown exceptional anti-cancer potency against LC; nonetheless, they still remain undisclosed. We believe that this assembled data would globally inspire scientists on the passing way of LC treatment.

Keywords: Apoptosis, Gene expression, Lamiaceae, Medicinal plants, mRNA, Phytochemicals

Introduction

Declaredly, lung cancer (LC) is reported to be the leading cause of cancer incidence and cancer associated deaths.¹ Threatening the lives of above two million people worldwide annually, LC places the second frequent cancer in men after prostate malignancy, and the top in women after breast cancer. LC was reported to be the leading cause of cancer mortality in 93 nations, involving China, Russia and the United States of America² which is estimated to account for 127 000 deaths by the end of 2023 merely in the US.³ Principally, LC comprises of small cell LC (SCLC) and non-small cell LC (NSCLC). Statistically, only 13% of all LC patients are SCLC cases, and majority of them (84%) are classified in NSCLC group.¹ Plant kingdom has been a well-known essential source of novel therapeutic agents against cancer.⁴ The prevailing chemotherapeutic agents have several therapeutic limitations since they affect healthy tissues, causing myriad health problems and adverse side effects; hence, there has been an escalating demand for alternative treatments. Naturally-derived anti-cancer agents obtained from plants have been an appealing source in the last decades. The secondary metabolites of plants have been investigated for their potential anti-cancer effects for many years. They have been shown to possess anti-cancer activities mainly by induction of apoptosis, inhibition of cancer cell growth, cancer cell cytotoxicity and by exerting antioxidant properties.⁵ A plant family of certain interest is Lamiaceae, which comprises several genera with substantial anti-cancer properties that have been found to have prominent potential against colon, lung, prostate and breast cancer cells in in vitro studies. Taken together, they enforce their cytotoxicity by selectively organizing cancer cell death, especially via apoptosis induction; Some were found to influence angiogenesis, as well.⁶ The majority of Lamiaceae family plants are essentially well-recognized for their aromatic properties. Pharmacological findings have uncovered that the essential oils (EO) of Lamiaceae plants also possess anti-cancer properties. Likewise, it has been reported that Lamiaceae plants comprise a diverse content of phytochemicals, predominantly consist of phenolic compounds, like flavonoids or benzoic acids, terpenoids and steroids.⁷ Regarding the progressing incidence of LC alongside the impressive worth of medicinal plants from the Lamiaceae family, the authors hereby aimed to compile and review the online literature upon plants of Lamiaceae family which have displayed remarkable in vitro and in vivo activities against LC. There have been many promising lead compounds against LC isolated from the plants of Lamiaceae family; thus far, many are self-abandoned and quite unlearnt that demand more investigations to lead to an exquisite, operational medicine. We trust that the collected data could assist experts all across the world in searching for new active phytochemicals against LC. It is assumed that this review could assist and inspire scientists and researchers in the path of LC treatment.

Methods and Materials

We have included each studied plant of Lamiaceae to date that has been reported to exhibit activity against LC whether in in vitro or in vivo studies. Some of the plants with very minor or ignorable cytotoxicity were excluded from this review. The papers with invalid registration properties or lacking proof of proficiency were also excluded. The incorporated papers were published between the years of 1997 and 2023. The main search keywords for this review article were “lung cancer”, “Lamiaceae”, ”cytotoxic effect”, “anti-tumor” and “anti-proliferative” in Medline, Springer, Scopus, ScienceDirect and Google Scholar databases.

Plants with anti-cancer properties

In this section, the promising findings regarding LC from the studied plants are briefly described. The chosen plants are represented with no specific arrangement and are randomly ordered. The suggested mechanisms of plants anti-cancer features are detailed to the furthest extent. As a final point, the anti-cancer potency indicators (such as IC_50s) for each plant and a summarized content of the reviewed studies are tabulated separately.

Phlomis younghusbandii

A significant anti-inflammatory activity was reported from Phlomisoside F (PMF), an isolated glycoside from ethyl ethanoate extract of P. younghusbandii roots.^8,9 Lu et al confirmed the growth inhibitory impact of PMF on a NSCLC cell line, known as A549 cells. They reported that PMF restrained A549 cells invasion and migration (known as metastasis) in a time and concentration dependent manner.¹⁰ Apoptosis, one of the main mechanisms of cytotoxic activity of phytochemicals, can be provoked by both intrinsic and extrinsic pathways.¹¹ The release of specific mitochondrial proteins is in charge of triggering the intrinsic apoptosis pathway; on the other hand, the extrinsic corridor is activated mainly by death receptors.^12,13 A protein known as caspase-8 (cas-8) plays an important role in the extrinsic apoptosis pathway. In contrast, the activated cas-9 is a key factor in activation of the intrinsic pathway.¹¹ Both activated cas-8 and cas-9 can set off executioner caspases like cas-3 which will arouse death substrates and conclusively lead to apoptosis.¹⁴ It has been reported that expression of cas-3 and cas-9 are often restrained in cancer cells, including LC. Moreover, the B-cell lymphoma 2 (Bcl-2) protein families are an effective regulator of proapoptotic proteins release. Bcl-2 is a key anti-apoptotic protein, thus Bcl-2 overexpression leads to cell survival. Furthermore, Bcl-2-associated X protein (Bax), a pro-apoptotic member of Bcl-2 family, could essentially play a role on the mitochondrial membrane.¹⁵ Lu et al reported PMF to boost cas-3, cas-9 and Bax expressions while reducing Bcl-2 expression; thus, PMF provoke apoptosis in A549 cells via a mitochondria-mediated pathway. In addition, cyclooxygenase 2 (COX-2), a strategic enzyme in arachidonic acid metabolism, could enhance prostaglandin E2 (PGE2) formation.¹⁶ It was witnessed that PGE2 can increase Bcl-2 and interleukin-6 (IL-6) production, resulting in apoptosis inhibition; hence, exacerbating cancer progress.¹⁷ COX-2 and PGE2 can hasten LC development as elevated levels of COX-2 are frequently attested in LC patients.¹⁰ PMF could efficiently downgrade COX-2 expressions in A549 cells, signifying that this might be an alternative anti-cancer influence of PMF on LC.¹⁰

Scutellaria baicalensis

Baicalin, baicalein, oroxylin A, wogonin, wogonoside are deemed as chief constituents of S. baicalensis which were mainly obtained from plants’ roots and exhibited significant anti-cancer effects.¹⁸ S. baicalensis were studied in terms of signaling pathways and potential targets regarding LC; including suppression of proliferation by restraining the cell-cycle, apoptosis stimulation, blockade of cancer metastasis and overcoming drug resistance as well.¹⁸ Li et al compared the anti-tumor effects of S. baicalensis with cisplatin in four tumor xenograft models (A549, Lewis lung carcinoma (LLC), and two other human LC cell lines known as H460 and H411) and reported that the tumor inhibitory rate of S. baicalensis were almost neighboring the obtained results from cisplatin. Remarkably, baicalein and baicalin were more potent than cisplatin in H411 and H460 tumor models.¹⁸ S. baicalensis has already established a good reputation in Chinese medicine as an adjuvant to chemotherapy in LC treatment. Anti-cancer studies confirmed that crude ethanol extracts of S. baicalensis were selectively toxic to A549 and a human lung adenocarcinoma cell line known as SK-LU-1 cells.¹⁹ Flavones of S. baicalensis have been reported to cease various cancer cell lines, including NSCLC.²⁰ In vivo studies approved that treating H460 and A549 cells with baicalein, baicalin, and wogonin resulted in anti-proliferation and anti-angiogenesis impacts mainly by reducing expressions of inhibitors of differentiation 1 (Id1) protein, the epithelial-mesenchymal-transition (EMT)-related molecules (such as vimentin and N-cadherin), fibroblast growth factor receptor 2 (FGFR2) and vascular endothelial growth factor A (VEGF-A).^20,21 Park et al confirmed that the aqueous extract of S. baicalensis roots inhibited A549 cells growth and induced cell cycle arrest at G1 phase by downregulating cyclinD1, cyclin-dependent kinase 4 (CDK4) and matrix metallopeptidase (MMP) 2 productions.²² Moreover, Kim et al reported induced apoptosis in NSCLC cell lines H2087 and H358 following treatment of the aqueous extract of S. baicalensis roots. The reported anti-cancer mechanisms weredescribed as increasing cas-3 and phospho-AMP-activated protein kinase (AMPK), reinforcing poly ADP ribose polymerase (PARP) cleavage and decreasing mammalian target of rapamycin (mTOR).²³ Wang et al investigated the cytotoxic effects from ethanol extract of S. baicalensis rootson A549 cells; where, the extracts upregulated expression of p53 and downregulated expression of cyclinD1; resulting in malignant cells detention.²⁴ Furthermore, Gao et al reported that the ethanol extracts of S. baicalensis affected NSCLC cells by inducing apoptosis via downregulating expressions of cyclinA and upregulating expressions of p53 and Bax.¹⁹ Gong et al studied the toxic effects of the obtained extracts from S. baicalensis on two nicotine-induced NSCLC cell lines, A549 and H1299; all the extracts were reported to upregulate the expression of Bax and downregulate MMP2, MMP9, cas-3, bcl-2 and bcl-2/bax ratio. The extracts also accompanied anti-inflammatory activity in NSCLC cells by reducing expressions of nuclear factor kappa light chain enhancer of activated B cells (NF-κB), TNF-α, I-kappa B-alpha and IL-6.²⁵ Zhao et al reported the effects of isolated flavonoids baicalin, baicalein and wogonin from this plant on H1299 and A549 cells; where, growth, invasion and migration of NSCLC cells were extremely restrained.²⁶ They suggested that the combination of chemotherapeutic agents and flavonoids might be a prospective strategy for increasing the anti-cancer potential of LC treatment.²⁰ Another study revealed that first-generation epidermal growth factor receptor tyrosine kinase inhibitors known as EGFR TKIs, as erlotinib and gefitinib, substantially lessened tumor growth and expanded survival rate of NSCLC patients. Despite the valued merit of these drugs versus cancer, resistance develops less than a year after treatment begins. Ethanol extract of S. baicalensis diminished cell growth and induced apoptosis in EGFR TKI-resistant human NSCLC cell lines by suppressing STAT3 activity²⁷; consequently, it was put forward that the potential use of S. baicalensis as a novel therapeutic agent for LC patients with EGFR TKI resistance could be a promising lead.

Scutellaria barbata

There have been numerous reports regarding the anti-cancer effects of obtained extracts from S. barbata. A Study contended that ethanol extracts of S. barbata (SB)greatly inhibited A549 cells proliferation with IC₅₀ of 0.21 mg/mL. The chief mechanism of action was reported as provoking apoptosis.²⁸ In line with reports, Scutebarbatine-F, a diterpene alkaloid from SB, exhibited good cytotoxicity versus a range of human tumor cells. In addition to Scutebarbatine-F, SB was also reported to contain wogonin, baicalein, scutellarin, ursolic acid and b-sitosterol; all reported to have significant anti-tumor activities.²⁹ These promising anti-cancer compounds could be the key components for NSCLC treatment, considering that they are positively aiming for a number of targets such as Bax, iNOS, and P38.²⁹ In vitro studies further confirmed that baicalein oppose NSCLC via regulating certain vital proteins including COX-2, NF-κB, Bax, extracellular signal-regulated kinase (ERK) and CDK1.²⁹ In vivo anti-tumor activity of baicalein were also studied, confirming baicalein as a considerable anti-cancer nominee for LC.²⁹ The results of another study supported the significant cytotoxic effects of SB on particular LC cell lines which were remarked with IC₅₀s between 0.1-0.8mg/mL. The suggested anti-cancer mechanisms were as a result of multiple apoptotic pathways regulations, involving p53 activation and/or EGFR inhibition.³⁰ Additionally, the isolated polysaccharides from SB have been reported to have anti-tumor effects as well. An extremely invasive and metastatic LC cell line, 95-D, was treated for exploring the underlying mechanism(s). The results indicated that these polysaccharides directly regulated the c-Met signaling pathway and the anti-tumor effects were mainly due to their anti-proliferation and anti-angiogenesis properties.³¹ Furthermore, hypoxia-induced factor 1-alpha (HIF-1α) is a transcription factor that increases invasion in cancer cells by stimulating the metastasis-related gene expression in hypoxic conditions. SB was reported to lessen the HIF-1α expression level and VEGF secretion in cancer cells; consequently, leading to its anti-angiogenesis effects.³²

Melissa officinalis

The tiniest analyzed concentrations of lemon balm leaves extract were reported to considerably reduce the viability of A549 cells.³³ It has been reported that M. officinalis enforce anti-cancer activity on multiple cancer cell lines, including LC. The active anti-cancer components of M. officinalis demonstrate their cytotoxic effect through several mechanisms including anti-proliferation, anti-angiogenic, anti-apoptotic, cell cycle arrest, and by possessing antioxidant properties.³⁴ In a survey by Jahanbin et al, M. officinalis aqueous extract significantly downregulated telomerase reverse transcriptase (hTERT) and VEGF-A in A549 cells indicating that M. officinalis exerted its anti-proliferative effects partially via parallel downregulation of both hTERT and VEGF-A expressions.³⁵ M. officinalis prevents angiogenesis, which is via inhibition of MMP9 and VEGF. Besides, expression levels of neovascularization elements such as FGF-2, MMPs (MMP9 and MMP2), and VEGF-A, -B, -C, -D declined as a result of M. officinalis treatment.³⁶ Notably, high anti-angiogenic activity of M. officinalis was linked its excessive anti-telomerase activity. It was concluded that the alteration of hTERT and VEGF-A gene expressions can be considered as a common target in LC.³⁵ Moreover, M. officinalis displayed a powerful free radical scavenging potency, as much as 10 folds greater than vitamin C.³⁷ Elsewhere, an In vivo study on rats revealed that oral ingestion of M. officinalis extractssustained histologic properties of heart tissue cells following doxorubicin-induced damage. Sousa et al investigated the effects of M. officinalis EOon A549 and four other cancer cell lines. It was attested that EO possess significant antioxidant potential.^37,38 Moaca et al studies concluded that rosmarinic acid (RA) a well-known phenolic compound from M. officinalis was responsible for the plants anti-migratory effects.^39,40 Jahanban-Esfahlan et al evaluated the anti-tumor effect of Lemon balmdifferentextracts, on H460 and two other cancer cell lines; reporting the ethanol extract as the most effective, and H460 cell line as the most affected cells.³⁵ They concluded that M. officinalis dose-dependently affected the cell cycle profile of H460 cells. By scrutinizing the expression levels of the proteins engaged in cell cycle and apoptosis, it was revealed that proteins responsible for triggering apoptosis, such as p53, cytochrome C, and Bax intensified upon M. officinalis ethanol extract treatment. The apoptotic activity of Bcl-2 protein can be regulated by p53 as a tumor suppressor protein. Subsequently, cytochrome C was found to endorse the caspase cascade. These proteins regulated apoptosis via mitochondrion permeability alteration.³⁴ The results of another study confirmed that among all the studied M. officinalis extracts and cancer cell lines, the ethanol extract presented the highest anti-tumor activity and H460 cells were reported as the most sensitive cells. Treating the H460 cells with ethanol extract followed a reduction in pro-cas-3 and an upsurge in p53 expressions.⁴¹ Cytotoxicity of different doses of M. officinalis extracts towards different cancer cell lines including A549 cells was evaluated by Jahanban-Esfahlan et al where, in all assessed cancer cell lines, M. officinalis extract reduced the cell viability to values below 33% (all the obtained IC₅₀ values were remarkably below 5μg/mL). The average growth inhibition of A549 cells was reported to be 77.8%.⁴²

Ocimum gratissimum

Chen et alinvestigated the cytotoxic effects of aqueous extract of O. gratissimum (OGE) on A549 cells and the alterations provoked by OGE in these cells. It was discovered that OGE dose-dependently decreased the viability of A549 cells via inducing DNA condensation, resulting to cell shrinkage. Other parallel studies reported that OGE boosted initiation of cas-3, cas-9 and cas-8 and raised apoptotic peptidase activating factor 1 (Apaf-1) and Bcl-2 antagonist killer 1 (Bak) protein levels; contrarily, OGE declined Bcl-2 expression. In addition, OGE hindered the phosphorylation of ERK; however, it enhanced the phosphorylation of p38 MAP kinase and c-Jun N-terminal kinase (JNK). In conclusion, Chen et al contended that OGE treatments considerably dropped A549 cells viability by affecting both wings of apoptotic and anti-apoptotic pathways through a combined effect of provoking apoptotic signaling and suppressing the anti-apoptotic signaling.⁴³ Cytotoxicity of oleanolic acid isolated from O. gratissimum has been investigated against six cancer cell lines including A549; where, oleanolic acid exhibited bioactivity against all studied solid tumor cell lines.⁴⁴ Elsewhere, OGE induced apoptosis in A549 cells by modulating some cell cycle regulators and apoptosis-related factors, concerning with drug resistance.⁴⁵

Ocimum sanctum

The chemopreventive effects of O. sanctum, Tulsi, have been evidently reported through the past Studies. Previous studies confirmed that Tulsi prevented LC by different mechanisms of action such as possessing antioxidant activity, inducing apoptosis and preventing neovascularization.⁴⁶ The effect of ethanol extract of O. sanctum (EEOS) in A549 cells was studied; where, it substantially reduced the extracellular connection of A549 cells, leading to cell death. EEOS induced DNA condensation as well. Furthermore, EEOS was able to induce apoptosis via up-regulation of cas-3 expression, increased reactive oxygen species (ROS) production, and diminished Bcl-2 activity. Moreover, EEOS also blocked expressions of superoxide dismutase 2 (SOD2) and glutathione peroxidase (GPx). In brief, these results proved that EEOS encouragingly was active against A549 cells through different mechanisms.⁴⁷ Elsewhere, the cytotoxic activity of EEOSin H460 cells was evaluated in vitro; it was seen that with higher concentrations of the extract, more prooxidant property was observed. The study concluded that EEOSanti-cancer activity was as a result of declining cell proliferation, modification in mitochondrial membrane potential, increasing ROS production and inducing apoptosis in H460 cells.⁴⁸ Osteopontin (OPN) is a crucial molecular target in cancer management. In a study, EEOS was used to clarify the anti-metastatic mechanism of OPN in H460 cells; where, EEOS expressively obstructed cell adhesion and cancer progression in H460 cells. EEOS effectively suppressed phosphatidylinositide 3-kinases (PI3K), urokinase plasminogen activator (uPA), EGFR and COX-2 expression levels and declined phosphorylation of Akt in OPN treated H460 cells. Phosphorylation of Akt leads to downstream initiation of the signaling molecules such as mTOR and p70S6K resulting to improved protein synthesis, proliferation and thus, survival. What is more, EEOS meaningfully reduced VEGF production and MMP9 activity in OPN treated H460 cells as well. In particular, Kwak et al explained the anti-metastatic mechanism of EEOS, which was declared to be facilitated by inhibition of PI3K/Akt in OPN treated H460 cells.⁴⁹ The apoptotic mechanism of EEOS was also investigated in A549 cells by Joseph and Nair; where, EEOS presented activity against A549 cells. EEOS released cytochrome C into cytosol, increased the sub-G1 population, cleaved PARP, and concurrently mounted cas-9 and cas-3 levels. EEOS also increased Bax/Bcl-2 ratio and restrained phosphorylation of Akt and ERK in A549 cells.⁵⁰ A recent research conducted on O. sanctum for exploring its anti-cancer potential, discovered that EEOS could act as both an anti-proliferative and an apoptotic agent in A549 cells. This study revealed that the active phytoconstituents of O. sanctum were chiefly quercetin and eugenol that essentially interacted with the active sites of the αvβ3 integrin, α5β1 integrin, cas-3, cas-9, and VEGF. As observed, hydrogen bonds and Pi-alkyl and Pi-cation interactions were engaged between the phytoconstituents and the active sites. Besides, in vitro studies confirmed the anti-proliferative effects of the EEOS against A549 cells.⁵¹ In a study, EEOS significantly inhibited cell adhesion, invasion and MMP9 activity in LLC tumor models, indicating the importance of MMP9 in anti-metastatic character of EEOS. Notably, it was also discovered that EEOS could dose-dependently improve the antioxidative activities of enzymes such as SOD2, catalase and GPx. Taken together, these results supported the exquisite anti-metastatic strength of EEOS.⁵²

Origanum compactum

The anti-tumor potency of carvacrol, the main active component of O. compactum EO against LC was evidenced by restraining cell growth in A549 cells. EO was also shown to be effective for its anti-mutagenic effects. O. compactum EO exhibited strong ability to inhibit urathane-induced mutagenesis.⁵³ A number of studies have reported the antioxidant activities of O. compactum extracts and EO. Recent studies have demonstrated the anti-cancer activity of O. compactum as an apoptosis inducer in A549 cells. Apoptosis induction was instructed by activation of caspase signaling which was set off by modulation of Bcl-2 family proteins. Among the EO constituents, thymol was frequently reported to have cytotoxic effects in LC cell lines. The cytotoxicity was as a result of DNA shrinkage and cell cycle arrest in G0/G1 phase. Another known compound from O. compactum EO known as carvacrol which is an isomer of thymol, showed a similar activity against LC cell lines.⁵⁴ Another study was conducted to explore the anti-proliferative effect of O. compactum extract on two human cancer cell lines, A549 and SMMC-7721 hepatoma cells. Contrary to SMMC-7721 cells, treating A549 cells with O. compactum extract resulted in a remarkable increase in activation of cas-3 which signaled provocation of the caspase signaling pathway apoptosis.⁵⁵

Salvia miltiorrhiza

Tanshinone (Tan) IIA has been the most studied compound among all the isolates from S. miltiorrhiza, thanks to its abundance in the herb. Tans exhibit diverse pharmacological activities, including anti-cancer property.⁵⁶ The cytotoxic effects of Tan IIA on several LC cell lines including A549, H460, H146, A-427, H838 and SPC-A1 has been frequently reported.^57,58 Tan IIA halted cell proliferation in LC cell lines in the midst of mitosis in a concentration and time dependent manner mainly via disrupting the mitotic spindle, consequently setting of cells to initiate apoptosis through the mitochondria-mediated apoptotic pathway.⁵⁹ Likewise, a further study testified that Tan IIA induced autophagic cell death in H460 cells.⁵⁶ NAD(P)H quinone dehydrogenase 1 (NQO1) is an encouraging target in cancer therapy. It was reported that NQO1 might be a potential target of Tan IIA in LC since the anti-cancer effects of Tan IIA were reversed by a specific NQO1 inhibitor treatment.⁶⁰ Collectively, the data clearly have shown that Tan IIA have the potential to considerably restrain multiple cancer lines with micromolar IC₅₀ levels; comparable with those of acknowledged anti-cancer agents, for instance curcumin, quercetin, and berberine.^61,62 Cryptotanshinone (CPT) isolated from S. miltiorrhizawas found to possess cytotoxic and anti-migration effects toward several LC cell lines (SPC-A1, CL1–5, H1299, A-427, H23, and A549). CPT also sensitized cancer cells to a wide extent of anti-cancer drugs such as doxorubicin, etoposide, cisplatin and 5- fluorouracil.⁶³ Another promising anti-cancer compound, named Tan I, was cytotoxic to a set of LC cell lines (SPC-A1, CL1–5, H1299, H23, A549, CL1–0 and CL1–5) mainly by inducing apoptosis. Tan I was reported to potentially inhibit the proliferation and invasion of CL1–5 cells. Tan I also efficiently inhibited an enzyme named gelatinase in CL1–5 cells in vitro and reduced tumor growth and metastasis in CL1–5 tumor model in SCID mice.⁶⁴ Additionally, Tan I restrained interleukin-8, the angiogenic factor involved in cancer metastasis by attenuating the DNA-binding activity of activating protein-1 and NF-κB.⁶⁴ In H1299 lung tumor animal model, Tan I (200 mg/kg) increased apoptosis by 193% and decreased tumor growth by 34%, neovascularization by 72% and metastases by 85%.⁶⁵ In a transgenic mice model LC, Tan I could appreciably reduce tumor growth by downregulation of Cyclin A, Cyclin B and VEGF protein expressions.⁶⁶ Recent literature have shown that dihydrotanshinone (DHT) I isolated from S. miltiorrhiza inhibited human LC cell line SPC-A1 cell growth in a concentration and time dependent manner superior than CPT, Tan I and Tan IIA.⁵⁶ It was reported that the cytotoxic potential of DHT I might be linked with HIF-1α accumulation reserve.⁶⁷ DHT I also induced DNA cleavage in in vitro studies via triggering topoisomerase I activity as efficient as camptothecin.⁶⁸ A major water-soluble compound isolated from S. miltiorrhiza, named danshensu, significantly was reported to improve the radiotherapy prognosis in LLC xenografts in mice. Danshensu improved tumor microcirculation and remodeled tumor vasculature; implying that danshensu might potentially hinder neovascularization.⁶⁹ Another study demonstrated that Tan compounds from the methanol extract of S. miltiorrhiza roots suppressed the growth of a LC cell line named Glc-82 both in vivo and in vitro as a result of provoked apoptosis through the mitochondrial-mediated pathway and PTEN-modulated inhibition of PI3K/Akt pathway.⁷⁰ Another study has revealed that apart from suppressing lung tumor growth in mice, salvianolate (isolated from S. miltiorrhiza) also downregulated expression levels of ATP7A and ATP7B, which are key proteins in cancer progression and chemotherapy of LC. This study attested that salvianolate could considerably decrease the tumor growth of xenograft nude mice⁷¹; announcing salvianolate as a promising compound for treatment of LC.

Salvia rosmarinus

Rosemary extract (RE) treatment on A549 cells lead to a substantial decline in cell viability with an IC₅₀ of 15.9mg/mL. The anti-cancer effects of RE was reported to be similar with resveratrol, a renowned phytochemical with potent anti-cancer properties.^72,73 Colony formation is one of the many strategies of cancer cells in order to survive the destructive impacts of anti-cancer agents or critical environments. Remarkable restriction of colony formation was observed with even as low concentrations as 2.5mg/mL of RE. At 10mg/mL concentration of RE, almost total inhibition of survival was documented. Treating RE resulted in 100% upsurge in cleaved PARP levels in A549 cells, signaling enhanced apoptosis stimulation by RE. Moreover, RE significantly inhibited phosphorylation of Akt and mTOR and total levels of these proteins in A549 cells.⁷⁴ All things considered, it has been suggested that RE has of note anti-cancer property and could potentially hold down A549 cancer cells.

Salvia hypargeia

Ulubelen et al investigated the cytotoxicity of S. hypargeia on different panels of cancer cells. The crude acetone extract obtained from S. hypargeia rootswas cytotoxically active in all studied cell lines including a LC cell line, LU1. Among 13 isolated compounds, the anti-cancer activity of 8 isolates were investigated; reporting that the two isolates, identified as 6a-hydroxysalvinolone and taxodione, demonstrated more potent cytotoxic activity than others against LU1 cells.⁷⁵

Salvia leriifolia

Tundis et al described the isolation and identification of a sesquiterpenoid compound known as buchariol and the flavanone, naringenin from S. leriifolia and examined their cytotoxic activity opposed to several human tumor cell lines including a particular NSCLC cell line known as COR-L23 and the A549 cells.The EO isolated from S. leriifolia aerial parts displayed a strong inhibitory activity towards COR-L23 cells.⁷⁶ The dichloromethane extract was reported to be the most active extract against the studied cell lines with IC₅₀ values ranging from 28.1 to 86.2 mg/mL. The anti-cancer activity of the two mentioned isolates, buchariol and naringenin was also studied. Buchariol isolated from the dichloromethane extract presented a significant cytotoxic activity towards A549 cells with an astonishing micromolar level IC₅₀ even lower than the positive control, vinblastine (as shown in Table 1).⁷⁶ These results may encourage further studies on this sesquiterpene as a lead compound against LC. The ethyl acetate extract also reported to possess a respectable cytotoxic activity against COR-L23 cells. As well, the flavanone naringenin, isolated from the ethyl acetate extract, exhibited interesting cytotoxic effects against COR-L23 cells. Notably, the positive control vinblastine was less potent than naringenin against all the studied tumor cell lines. Sabarinathan et al demonstrated that supplementation of laboratory animals with this flavanone modulated the Bcl-2/Bax ratio and upregulated cas-3 and cas-9.⁷⁷ In recent years there has been a grown interest in naringenin as a potent anti-cancer flavonoid since numerous reports of its potent cytotoxic activity were documented in the literature.

Salvia prionitis

A diterpenequinone compound named salvicine, obtained from S. prionitis by Zhang et al, was found to possess potent anti-tumor activity. The reported convincing doses (tumor growth inhibition above 30%) for LAX-83 (human lung adenocarcinoma) and A549 cells were 20 and 30 mg/kg, respectively.⁷⁸ The particular cytotoxicity of salvicine was connected to its apoptosis stimulus nature. Salvicine was reported to exhibit a respected cytotoxic activity on multidrug-resistant (MDR) cancer cell lines by decreasing the expression of multidrug resistance mutation 1 (MDR-1) mRNA in MDR cells. Salvicine behaved as a topoisomerase II exterminator which was further confirmed that its cytotoxic activity was as a result of its ability to stabilize DNA strand breaks and consequently generating anti-cancer effects.⁷⁹ Chang et al investigated the roots of S. prionitis and successfully isolated 6 novel compounds; Among them, prionoid E demonstrated remarkable anti-proliferative activities upon A549 cells.⁸⁰

Salvia yunnanensis

Twelve diterpenoids were isolated from the roots of S. yunnanensis byXia et al and all of them were assessed for potential cytotoxicity against several cell lines including H460 cells. 6α-hydroxysugiol, sugiol, and Tan IIA were the three compounds that exhibited slight anti-cancer activities against LC cell lines.⁸¹ A similar study was conducted on S. yunnanensis roots, following to isolation of six abietanes, salyunnanin A–F, together with 40 known analogues; moreover, all isolates cytotoxicity against several cancer cell lines were studied. Danshenol A and 6ahydroxysugiol, were reported to demonstrate substantial cytotoxicities upon H460 cells with IC₅₀ values of 11.8 and 7.43 µM respectively.⁸²

Salvia lachnostachys

Previous studies have reported the isolation of several terpenoids from S. lachnostachys includingoleanolic acid, ursolic acid and a diterpene known as fruticulin A.⁸³ Oliveira et al evaluated the ethanol extract of S. lachnostachys leaves and its fractions for any potential in vitro cytotoxic activity against several cancer cell lines including H460. The extract and its fractions illustrated a moderate cytotoxicity against H460 cells. Among fractions, the hexane eluted one was the most potent. Oliveira et al successfully isolated two known diterpenes, identified as fruticulin A-B by chromatographic separation; the anti-cancer effects of both of these diterpenes were inspected against several cell lines, reporting fruticulin Aas a potential cytotoxic compound with an GI₅₀ value of 7.4 µM against H460 cells.⁸⁴

Salvia ballotiflora

In a study, aerial parts of S. ballotiflora were phytochemically analyzed by Esquivel et al in which they isolated eleven diterpenoids together with an anti-proliferative evaluation against several human cancer cell lines including SK-LU-1. Results of the study revealed that a compound named anastomosine was foundto be very toxic to SK-LU-1 cells, 7α-acetoxy-6,7-dihydroicetexone was moderately active against SK-LU-1 and an aromatic diterpenoid named 6,7,11,14-tetrahydro-7-oxo-icetexon proved to be very toxic to the complete panel. Besides, anastomosine and 7α-acetoxy-6,7-dihydroicetexone were identified as the most active molecules in terms of SK-LU-1 cells; nonetheless, the calculated IC₅₀ values indicated that 7α-acetoxy-6,7-dihydroicetexone and anastomosine came close to the positive control, adriamycin, in potency.⁸⁵ Esquivel et al exploration attested that compounds 7α-acetoxy-6,7-dihydroicetexone and anastomosine deserved further studies on their anti-cancer properties. In another comparable research, a hexane-washed chloroform extract of S. ballotiflora together with four isolated diterpenoid compounds were tested for their potential cytotoxic activity against three tumor cell lines and A549 cells. The hexane-washed chloroform extract revealed the supreme cytotoxic activity on A549 cells with parallel activity compared to cisplatin.⁸⁶

Ajuga ovalifolia

Liu et al investigated cytotoxicity of a new abietane diterpenoid, 3-acetoxylteuvincenone G (3-AG), toward A549 cells reporting a significant rise in the amount of early and late apoptotic A549 cells through activation of downstream cleaved cas-9, accompanied by upregulation of upstream cleaved cas-9, cleaved cas-3, and in due course cleaved PARP. Likewise, administration of 3-AG caused a noticeable upsurge in the level of cas-3. Conclusively, 3-AG induced cas-3-medicated apoptotic pathway in A549 cells. The over-expression of protein tyrosine phosphatase 2 (SHP2) is being observed in numerous mankind tumors; thus inhibition of SHP2 activity brings the growth of tumor cells under control. 3-AG was documented that not only it specifically inhibited SHP2 catalytic activity, but also suppressed phosphorylation of SHP2 and SHP2 expression in A549 cells. In brief, 3-AG restrained A549 cell proliferation whilst inducing cell apoptosis via regulation of SHP2-ERK1/2 and SHP2-AKT pathways.⁸⁷ Therefore, 3-AG might be considered as an inexperienced optimistic SHP2 inhibitor for treatment of NSCLC. Further studies conducted on A. ovalifolia indicated that another isolated abietane diterpenoid, Ajuforrestin A, exhibited direct inhibitive activity on SHP2 catalytic domain. Treating A549 cells with Ajuforrestin A significantly restrained cancer cells proliferation as the occasion of cell apoptosis via inhibiting the SHP2–ERK/Akt pathways.⁸⁸

Isodon silvatica

As far as we know, Isodon spp. are rich in diterpenoid compounds that are renowned for showing anti-tumor bioactivity.⁸⁹ In a study on I. silvatica, acetyl-macrocalin B (A-macB) was isolated from the plant extract, where its cytotoxic activity against NSCLC were evaluated underlying its mechanisms of action. A-macB successfully restrained H1299 and A549 cells proliferation, generated apoptosis and stalled cells in the G2/M phase. The related mechanisms were incitement of ROS production and activating the p38 mitogen-activated protein kinase (MAPK)-mediated, cas-9-dependent pathway of apoptosis. NAC and a certain p38 inhibitor agent named SB203580 could efficiently incapacitate A-macB, consequently arresting apoptosis. A-macB induced G2/M phase arrest by activating the checkpoint kinase (CHK) 1/2-Cdc25C-Cdc2/cyclin B1 axis. Furthermore, A-macB admirably inhibited tumor growth in a mouse xenograft model deprived of evident toxicity for normal tissues.⁹⁰ According to the obtained data in terms of efficacy and safety, we might propose A-macB as a prospective lead agent for additional investigations on anti-cancer drugs.

Lavandula dentata

The reported bioactivities of L. dentata EO were claimed to be due to the presence of monoterpenes mainly linalyl acetate and linalool.⁹¹ The EO was documented to possess cytotoxic properties. Justus et al conducted a study on L. dentata EO in its both gas and fluid phases to investigate its cytotoxic effects on a NSCLC cell line Calu-3 cells, and reported further observations of its anti-cancer properties. Promising results were obtained; L. dentata EO treatment resulted in a substantial decline of Calu-3 cells viability and as reported, up to 84% of growth inhibition was witnessed in a time-dependent manner. Both necrosis and apoptosis rates were remarkably raised in Calu-3 cancer cells upon treatment of lavender EO in its gas phase.⁹²

Plectranthus amboinicus

Previous studies on P. amboinicus stem extract revealed that the plant contains high quantities of phenols, proanthocyanidins and flavonoid compounds such as RA, gallic acid, caffeic acid, rutin and quercetin. These polyphenol compounds have been reported to link up with the antioxidant and anti-tumor properties.⁹³ A study was conducted on P. amboinicus methanol extracts to determine its anti-proliferative effects on A549 cells; reporting the extract to possess moderate anti-cancer activity on the studied LC cell line.⁹⁴ Elsewhere, the anti-cancer activity of P. amboinicus EO on lung metastasis was evaluated; reporting the EO to possess a considerable cytotoxic activity on a highly metastatic (mostly invade towards lungs) melanoma cell line named B16F-10. A major reduction of tumor development in lungs was reported in mice upon the EO treatment as an indicator of P. amboinicus EO anti-lung metastatic effect. Plus, the EO refined lung cells microenvironment. Carvacrol and thymol were frequently reported for their potential anti-cancer properties in different studies and were both reported to be broadly present in P. amboinicus EO.⁹⁵ Novel cancer therapies emphasize the anti-angiogenic property as an exceedingly appreciated strategy in treatment of cancer. It was reported that P. amboinicus EO efficiently prohibited neovascularization in tumor environment which is assumed to be due to the presence of thymol and carvacrol.⁹⁶

Pogostemon auricularius

Three terpenoids known as pogostemins A-C were isolated from P. auricularius by a study conducted by Nguyen et al; cytotoxicity of these isolates was assessed against a panel of cancer cell lines including SK-LU-1. It has been reported that these meroterpenoids indicate signs of cytotoxicity as opposed to all studied cancer cell lines.⁹⁷ To explain the related anti-cancer mechanism of pogostemin A and how it provoked apoptosis in SK-LU-1 cells, the effects of pogostemin A on cas-3 were investigated. It was proven that cas-3 activity increased significantly upon pogostemin A treatment.⁹⁸

Perilla frutescens

Wanisa et al conducted a study to explore the antioxidant effects of P. frutescens leaves extract (PLE) and investigate its anti-inflammatory effects on TNF-α- treated A549 cells. PLE was reported to demonstrate a significant anti-inflammatory effect in aroused A549 cells mainly via prevention of ROS formation and by decreasing expressions of TNF-α, IL-1β, IL-8 and COX-2.⁹⁹ PMFF is one of the environmental pollutants which mainly spread in the air as a result of forest fires. It is reported to induce inflammation, oxidative stress and metastasis in cancer cells due to the presence of polycyclic aromatic hydrocarbons. Perilla seeds contain a considerable amount of polyphenols, such as RA. Pintha et al investigated the antioxidative and anti-metastasis activities of RA rich fractions (RA-RF) isolated from perilla seeds and the principal mechanisms involved, in pre-exposed A549 cells to PMFF. It was reported that PMFF significantly triggered invasion, migration, ROS production, MMP9 activity, expression of inflammatory cytokines, Akt phosphorylation and lastly overexpression of c-Jun and p-65-NF-κB in malignant cells; events that all were suppressed by RA-RF. Plus, RA-RF reduced COX-2, IL-6, IL-8 and TNF-α expressions as well. Conclusively, RA-RF was described to exhibit its anti-metastasis properties via c-Jun, p-65-NF-κB, and Akt signaling pathways.¹⁰⁰ RA-RF was suggested to be introduced and utilized as an inhalation drug for prevention of lung inflammation and LC metastasis. El-Hafeez et al studied a modified isolated compound named 8-hydroxy-5,7-dimethoxyflavanone from PLE which showed inhibitive activity on A549 cells. They documented that this isolated methoxyflavanone (PDMF) was able to notably inhibit cell proliferation of LC cell line A549 cells via induction of apoptosis through cell cycle arrest at G2/M phase. The PDMF could successfully increase the levels of anti-tumor agent p53 and its expression in cancer cells. PDMF also raised upregulation of apoptotic caspases, cas-9 and cas-3. These results supported that PDMF resembled to a functional LC-preventive plant-derived agent that triggered apoptosis through cell cycle arrest.¹⁰¹ El-Hafeez et al further studies on P. frutescens anti-cancer activity also revealed that PDMF could synergize with TKI agents and intensify their anti-tumor strength on A549 cells. The synergistic anti-tumor effect was fulfilled by induction of cell cycle arrest at both G2/M and G1 phases.¹⁰² The effects of PLE on two cancer cell lines, namely, HCT116 and H1299 (a colorectal cancer cell line and a LC cell line, respectively) were investigated. Treatment of these cells with PLE, dose-dependently inhibited cancer cells proliferation by 52-92% and completely abolished the colony formation in soft agar. Treatment with 350 μg/mL concentration of PLE resulted in multiplied population of sub-G1 cells in both studied cell lines, confirming its apoptosis-inducing character. Moreover, PLE effectively inhibited H1299 cells migration rate up to 58% and decreased both cell lines extracellular adhesion by 25-46%. Conclusively,PLE was introduced as a potential anti-cancer agent against LC.¹⁰³ Several other studies were performed on P. frutescens to probe its anti-cancer potency and confidently all of them reported a notable anti-cancer activity but only a few were described here.

Mentha piperita

The anti-cancer effects of M. piperita leaves EO was investigated upon several cancer cell lines and as it was reported, the EO was significantly active against SPC-A1 cells with a reported IC₅₀ value of 10.89 mg/mL.¹⁰⁴ Yücel et al explored the in vitro anti-proliferative effects of M. piperita EO in A549 cells; where, it was found to effectively decrease the viability of NSCLC cells with respectable low IC₅₀ values. As reported, peppermint EO also changed the morphology of A549 cells, resulting to changes that might be interpreted as a pro-apoptosis state.¹

Mentha pulegium

Farnam et al inspected the ethanol extract of M. pulegium aerial parts and its anti-cancer effects on two different cell lines; an invasive breast cancer cell line named MCF7 and the renowned A549 cells representing for LC. The ethanol extract exhibited degrees of cytotoxicity on both ofthese cell lines in a dose-dependent manner. For A549 cells, IC₅₀ was reported about 49 μg/mL; as reported, the MCF7 cells proliferation was halted at G2/M phase; conversely, the A549 cells detained in G0 phase of the cell cycle after treating with M. pulegium extract.¹⁰⁵

Four other Mentha spp.

In an in vitro study, Sharma et al evaluated the anti-cancer potential of several Mentha spp. namely, M. arvensis, M. longifolia, M. spicata and M. viridis versus multiple cancer cell lines including a bronchioalveolar carcinoma cell line, known as NCI-H322 and A549 cells. Methanol extracts of these Mentha spp. were reported to show promising signs of cytotoxic effects (up to 70-97% of growth inhibition) upon NCI-H322 cells; notably, all methanol extracts of these Mentha species were more potent than the positive control paclitaxel against NCI-H322 cells.¹⁰⁶

Polygonum cuspidatum

Cachexia, one of the most frequent risk factors for increased mortality of cancer, is briefly characterized as degeneration of body fat and muscles. The effects of emodin – a highly abundant compound in P. cuspidatum extracts – on cancer-induced cachexia, were explored in an in vivo study by Fang et al using A549 tumor-bearing mice. Emodin-contained extracts were reported to significantly reduce cachexia symptoms in lung tumor models.¹⁰⁷ Elsewhere, P. cuspidatum roots extracts were investigated in case of possessing cytotoxic activity on human LC cells. It was reported that the extracts inhibited both H1650 and A549 cells proliferations by inducing apoptosis, suggesting P. cuspidatum as a cytotoxic plant against LC.¹⁰⁸ Resveratrol, a phytoalexine compound abundantly found in P. cuspidatum, was reported to appreciably downgrade tumor volume, tumor weight and metastasis (56%) in LLC tumor model mice at promising doses ranging from 2.5 to 10 mg/kg. Resveratrol successfully hindered DNA synthesis in LLC tumor cells with an IC₅₀ value of 6.8mmol/L. Moreover, at concentrations of 10–100mmol/L, resveratrol was reported to appreciably inhibit formation of capillary-like tubes in an in vivo study; introducing it as a potential anti-angiogenic substance. Elsewhere, besides confirming the anti-tumor and anti-metastatic effects of resveratrol, it was supposed that inhibition of DNA synthesis could be the key mechanism for its anti-cancer effects.¹⁰⁹

Vitex negundo

Xinet alinvestigated the cytotoxic activity of a lignan comprised blend isolated from V. negundo, on a variety of cancer cell lines including A549 cells. The observed IC₅₀ for the A549 cells was a respected value of 10.84 µg/mL. Lignans extracted from V. negundo were reported to exhibit their cytotoxic activity through restraining LC cells at G2/M cell cycle phase and apoptosis provocation.¹¹⁰

Nepeta cataria

Fan et alinvestigated the effect of total flavonoids isolated from N. cataria (TFS) on A549 cells and reported its anti-tumor effect on A549 cells. Both necrosis and apoptosis rates of the studied cells were meaningfully superior to those in the control group and this effect was in a concentration and time dependent manner. It was reported that TFS meet its anti-cancer effects through regulating the PI3K-Akt signaling pathway and by interrupting the expression of microRNA-126¹¹¹; suggesting that the merit flavonoids of N. cataria might be used as a novel therapeutic agent for treating LC.

Thymus spp.

Oliviero et al probed the anti-inflammatory and cytotoxic activity of hydroalcohol extracts of T. vulgaris in H460 cells and paralleled the results with those obtained from normal tracheal and bronchial cells. Interestingly, the selective cytotoxic effect of the extract on H460 cells in comparison to normal cells was documented. The reported capability of the extract in modulating the cytokines IL-1β and IL-8 and interacting in NF-κB p65 and NF-κB p52 pathways - that all led to prevention of angiogenesis, tumor progress and metastasis - were magnificent.¹¹² Elsewhere, the anti-cancer activity of three thymus species EO on multiple cell lines including H460 (representing for LC) was investigated; where, thymol was reported to be the chief component in all studied EOs. The isolated thymol exhibited the most activity against H460 cells with an IC₅₀ value of 37.17µg/mL.¹¹³ Elsewhere, Zu et al investigatedthe cytotoxic effects of 10 plants EOs on cancer cell lines including A549 cells. The thyme EO selectively displayed the highest anti-proliferative activity against A549 cells among all studied EOs with an IC₅₀ value of 0.011%v/v.¹¹⁴

Anisomeles indica

Basappa et al phytochemically investigated A. indica leaves EO and surveyed its biological properties. The anti-cancer activity was analyzed by assessing cytotoxic effects on cancer cells in four cancer cell lines including A549, on behalf of LC. Admirably, inhibition of cell proliferation in all investigated cell lines was endorsed. A549 cells growth inhibition was achieved with IC₅₀ value of 63.36 µg/mL.¹¹⁵ Ovatodiolide isolated from A. indica, was reported to trigger DNA damage followed by increased ROS production. Moreover, ovatodiolide treatment could inhibit cell proliferation in both H1299 and A549 cells by inducing apoptosis with outstanding IC₅₀ values of 10 and 4µM after 48h of treatment. There are some identified proteins categorized as DNA damage-related molecules, such as ATM, ATR and CHK1/CHK2, that their expressions raise following DNA damage. It was reported that levels of these proteins upraise after ovatodiolide treatments in cancer cells. Furthermore, ovatodiolide efficiently prompted apoptosis via both extrinsic and intrinsic pathways; succinctly said, raising p53, Bax, and death receptor 5 protein levels, decreasing Bcl-2 and Myeloid cell leukemia-1 (Mcl-1) expressions, and activating cas-3, cas-8 and cas-9 were the associated anti-cancer mechanisms.¹¹⁶

Monarda citriodora

Thymol was reported to be the major (82%) component of M. citriodora EO (MCEO). The cytotoxic potential of MCEO in a leukemia cancer cell line known as HL-60 cells was documented. The reported mechanisms of action were through apoptosis and disruption of the PI3K/Akt/mTOR signaling cascade. Both MCEO and thymol inhibited the PI3K/Akt/mTOR signaling pathway and MCEO activity was reported to be significantly higher. Both MCEO and thymol, inhibited cell proliferation in A549 cells, as well. The reported mechanism of action for this cytotoxic effect was inducing apoptosis through both intrinsic and extrinsic pathways that were further confirmed by increased expression levels of death receptors (such as TNF-R1, Fas and cas-9) and subsiding the Bcl-2/Bax ratio.¹¹⁷

Teucrium polium

Haïdara et al investigatedaqueous extract of T. polium for its cytotoxic activity against NCI-H322 and A549 cells. The extract inhibited cell growth, deregulated cell cycle and induced a significant apoptosis rate in the studied LC cell lines. Bearing in mind that flavonoid compounds have a well-established anti-cancer property, it was proposed that the obtained results could be related to p53 protein and other regulators of cell death.¹¹⁸

Table 2 briefly depicts the obtained IC₅₀ values or other potency indicators of the studied Lamiaceae plants with potential activity against LC. A succinct summary of all studied papers, including the studied compound(s), study results, and possible anti-cancer mechanism(s) of action are provided in Table 3.

Concluding remarks

Among all the studied medicinal plants of Lamiaceae, effective in LC, 31 plants were chosen for this review considering their potency and efficacy. Different spp. of Salvia, Thymus, Scutellaria, Ocimum and Mentha were reported to exhibit promising activities against LC both in in vitro and in vivo studies. So long as possible, the mechanisms of action for the corresponding anti-cancer effects were described as well. It was witnessed that Lamiaceae plants affect LC by several different noteworthy mechanisms; such as, apoptosis induction in cancer cells through triggering both intrinsic and extrinsic mitochondrion-mediated apoptosis pathways, disrupting cell-cycle and suppression of cancer cell proliferation by aiming at multiple targets, regulate mRNA expression of some key apoptosis modulator proteins, blockade of invasion and metastasis by different mechanisms, for instance, with downregulation of VEGF-A, HIF-1α and hTERT secretions, as well as overcoming drug resistance for some cancer chemotherapeutic agents like TKIs. Although several plant extracts or pure isolated compounds are astoundingly potent against LC cell lines or tumor models, many of these invaluable elements are overlooked, and the studies remain incomplete, necessitating more effort for further investigations, delving deeper into the molecular mechanisms of how these phytochemicals inhibit lung cancer would be valuable, revealing specific signaling pathways or targets could guide future drug development. As regards, future research could be focused on both preclinical studies upon the potent phytochemicals and also on the toxic dosage of them to strengthen the evidence base knowledge. It is expected that this report would help scientists with having a better, concise attitude towards detailed evaluation of Lamiaceae plants’ potential for LC treatment.

Competing Interests

The authors declare no conflict of interest neither with a person nor an institute.

Ethical Statement

The whole study was registered at Tabriz University of Medical Sciences.

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