Curcumin, a phenolic compound derived from the Curcuma longa plant, has been demonstrated to control the expression of various growth factors in cells. Diferuloylmethane or curcumin also regulates the expression of kinases, inflammatory cytokines, transcription factors, cell cycle regulators, and apoptotic proteins (Giordano & Tommonaro, 2019). Curcumin has been used in treating prostate, cervical, uterine, and breast cancer with clinical trials in several trial phases (Giordano & Tommonaro, 2019). In pancreatic cancer, Diferuloylmethane downregulates the expression of NF-κB, miR-21, c-Myc, Hes-1, Stat-3, COX-2, CD-31, VEGF, Notch gene and upregulates the expression of p21 and p27 genes thereby suppress tumor growth (Bimonte et al., 2016). Curcumin inhibits the cell cycle in colorectal cancer by upregulating caspases and downregulating cyclin D1 and cyclin D3.

Additionally, it upregulates the expression of apoptotic genes like Bax while downregulating inflammation-related genes like TNF-α, cytokines, and NF-κB (Pricci et al., 2020). Similarly, various cell signal transduction pathways are targeted in breast cancer, lymphoma, leukemia, multiple myeloma, prostate cancer, and brain tumors (Liu and Chen, 2013; Giordano & Tommonaro, 2019). The IC50 value of curcumin using MCF-7 cell line of Human Breast Adenocarcinoma cells at 24, 48, and 72 h was 79.58, 53.18, and 30.78 nM respectively (p < 0.05). Mcl-1 gene product was also suppressed by the action of curcumin (Koohpar et al., 2015). There was a significant difference between inhibitory concentration IC50 value for curcumin and nano curcumin on cancer cell line MDA-MB231 of breast cancer cells, with nano curcumin having IC50 value at lower concentrations than curcumin with p < 0.01. Hence, nanotechnology is better for treating human breast cancer (Khosropanah et al., 2016). Moreover, curcumin-encapsulated nano-micelles had better cytotoxicity against cisplatin-resistant human oral cancer due to better cellular localization in these cells (Kumbar et al., 2022). For individuals with benign prostatic hypertrophy, a pilot product evaluation study was conducted to examine the effects of curcumin. Curcumin decreases signs and symptoms and enhances the quality of life. Curcumin has a limited bioavailability, although it is non-etheless used in clinical settings. A combination of curcumin and imatinib reduced nitric oxide levels in a randomized control trial of patients with chronic myeloid leukemia (Table 1). A phase II clinical trial of intestinal adenoma patients revealed no significant clinical response due to poor oral bioavailability (Tomeh et al., 2019).

Studies on chemoprevention in murine hepatoma cells showed that the -C=C-C=O moiety in curcumin analogs helps enhance the activation of Phase II detoxifying enzymes. The structural activity relationship (Figure 1) also revealed that, in prostate cancer cells, the conjugated ß-diketone moiety is essential for biological activity (Kaur, Kaur, and Bansal 2021). Adding two ortho-chloro groups in phenyl rings also helps reduce the multiplication of endothelial cells. Introducing the para-methoxy group in the phenyl ring is helpful in the anti-angiogenesis property of curcumin analogs. The anti-angiogenesis property is significantly diminished when the phenyl rings are swapped with pyridyl rings or when the phenyl rings are substituted with ortho chlorine groups (Lin & Lee, 2006). Recently, some curcumin derivatives have been developed where the phenolic–OH groups are entirely or partially substituted, or the diketo chain has been substituted on C4 carbon. Some of these compounds were able to block the expression of NF-κB in triple-negative breast cancer cells more potently than curcumin (Bonaccorsi et al., 2019). Another curcumin derivative, EF24 displayed improved anticancer efficacy compared to curcumin, higher bioavailability, and a slower metabolic rate (Nocito et al., 2021).

Podophyllotoxin can be extracted from vascular plants belonging to 60 different families, which include genera like Chaerophyllum aurium from the Apiaceae family and Justica heterocarpa from the Acanthaceae family. (Shah et al., 2021). A critically endangered plant, Podophyllum hexandrum of the family Berberidaceae rhizomes, processes several lignans which show anticancer activities (Arora et al., 2010). Various Podophyllotoxin derivatives have been synthesized to address drawbacks like systemic toxicity, drug resistance, and limited bioavailability (H. Fan et al., 2021). Etoposide, teniposide, and etopophos are semi-synthetic anticancer compounds derived from podophyllotoxin. These compounds have fewer side effects than podophyllotoxin (Changxing et al., 2020; Shah et al., 2021; Mishra et al., 2022). Due to systemic toxicity, drug resistance, and low absorption, nearly all podophyllotoxin derivatives were severely constrained in clinical therapy (Zhao et al., 2021). These drugs can efficiently deal with several malignancies, such as Hodgkin’s and non-Hodgkin’s lymphoma, multiform glioblastoma lymphoma, non-lymphocytic leukemia, Wilms tumors, testicular cancer, neuroblastoma and hepatocellular carcinoma (Yu, Che, and Xu 2017; Găman, Egbuna, and Găman 2020). Topoisomerase II activity is inhibited by etoposide, etopophos, and teniposide, which work by creating complexes with DNA and the enzyme. However, the cytotoxicity caused by teniposide is much more than etoposide due to the lesser potency of teniposide and more accumulation of teniposide in cells (B. H. Long 1992). Epipodophyllotoxin is ß confirmation derivative of podophyllotoxin. When 1.2, 3triazole acts as a linker with another pharmacophore moiety, they are categorized as Type II hybrids of epipodophyllotoxin (Xiao et al., 2020). The anticancer property of GL331, NK-611, TOP53, and NPF, as well as other podophyllotoxin compounds such as etopophos and teniposide, are supported by several investigations (Shah et al., 2021). The glucopyranose derivatives of 4-demethylepipodophyllotoxin (DMEP), known as Etoposide (VP-16) and Teniposide (VM-26), are preferred for high-dose chemotherapy treatment of lymphoma, particularly for those patients who experienced recurrence in incurable non-small cell lung cancer (Zhao et al., 2021). The negative consequences of VP16 therapy include genotoxicity and bone marrow suppression. The 3-year overall survival of radiation combined with VP-16/cisplatin was significantly higher than that of paclitaxel/carboplatin in the treatment of non-small cell lung cancer, and the median survival time was 23.3 months, according to the results of a phase III clinical study for the drug combination (Zhao et al., 2021).

Teniposide is more effective than etoposide and causes less damage to hematopoietic stem cells than etoposide (Motyka et al., 2023). 2,6-dimethoxy-4-(6-oxo-(5R,5aR,6,8,8aR, 9-hexahydrofuro [3′,4′:6.7]naphtho[2,3-day] [1,3]dioxol-5-yl)phenyl ((R)-1-amino-4-(methylthio)-1-oxobutan-2-yl)carbamate (DPMA) is a derivative of deoxypodophyllotoxin has more cytotoxic activity compared to etoposide. It also induces Bax and inhibits Bcl-2 expression (Motyka et al., 2023). Multiplication of human cervical adenocarcinoma HeLa cells in in-vitro cytotoxicity study was significantly suppressed by the nanoscale drug delivery system Graphene oxide-Polyethylene glycol disulfide prodrug of podophyllotoxin than those of 293T cells, which were taken from normal human kidney. This stemmed from the fact that cancer cells have much greater intracellular glutathione levels than other cells (Y. Liu et al., 2020). Consequently, a redesigned drug delivery mechanism lessens the cytotoxicity of podophyllotoxin derivatives. Hodgkin’s lymphoma patients are treated with etoposide and teniposide using various combinations of other drugs. They can be administered orally or by intravenous route. Myelosuppression, digestive issues, and baldness are toxicities seen during chemotherapy (Găman, Egbuna, and Găman 2020). Aiming the abnormally expressed genes in breast cancer cells, like p53, cyclin B1, Cdk1, VEGF-A, STAT-3, ERK1/2, and AKT-1 podophyllotoxin derivatives like 4ß-amidopodophyllotoxins induce cell cycle arrest. Similarly, by acting on CDK1 and Cyclin B1, podophyllotoxin-norcantharidin hybrids cause cell cycle inhibition and apoptosis (H. Fan et al., 2021).

The IC50 value for accessing the cytotoxicity of podophyllotoxin, picropodophyllotoxin, and deoxypodophyllotoxin (DPT) on colorectal cancer cells by using MTT assay was found to be 649.7, 532.1, and 56.1 nM respectively. In cell lines, namely HT29, DLD1, and Caco2, the IC50 value of DPT was 56.1, 23.4, and 26.9 nM, respectively, at 48 h of drug exposure. This was attributed to the fact that DPT destabilizes microtubules, increases the production of BAX protein, and suppression of production of Bcl-xL protein, leading to programmed cell death (Gamage et al., 2019). Similarly, JNC-1043, a podophyllotoxin derivative, has an IC50 value of 114.5 and 157 nM by using cell viability assay on HCT116 and DLD-1 cell lines of colorectal cancer cell lines at 72 h of drug exposure. Both JNC-1043 and gamma ionizing radiations had effects on increased mitochondrial ROS production (Kwon et al., 2022). For cell lines, namely NCI-H1299 and A549 cells of non-small cell lung cancer cells, the IC50 value of podophyllotoxin acetate was found to be 7.6 and 16.1 nM, respectively, at 72 h of drug exposure. This was due to the inhibition of microtubule polymerization and cell cycle arrest, ultimately leading to apoptosis (Choi et al., 2015).

The structural activity relationship (Supplementary File S1) revealed that both A and E rings are crucial for podophyllotoxin anti-cancer activity. Lactone from the D ring is preferred; the C4 position in the C ring can be modified with bulky groups, and modifications in the B ring are not tolerated (Xiao et al., 2020; X. Zhang et al., 2018; Reddy et al., 2018; Dong et al., 2016). A and D rings can be modified to increase biological activity. E ring shows orthogonal free rotation, which is necessary for the anti-tumor activity of the compound (Nagar et al., 2011).

Paclitaxel can be extracted from plants of the Taxaceae family, such as Taxus brevifolia, found in the Western United States; Taxus baccata, known as European Yew, Taxus cuspidata, known as Japanese Yew; Taxus wallichiana, Taxus chinensis , Taxus floridana, Taxus canadensis found in the Eastern United States, Taxus globosa, and plants of Betulaceae family namely Corylus avellana Known as the hazel plant is also a source of paclitaxel (Hodgson, 2012; Swamy et al., 2022). Taxus wallichiana is known as Himalayan yew and is located in the temperate Himalayas between 1800 and 3,300 m above sea level, as well as at the height of 1,500 m in the highlands of Meghalaya and Manipur (Juyal et al., 2014). Paclitaxel (generic name) was first synthesized from the bark of Taxus brevifolia and is commonly known as Western yew (Juyal et al., 2014). These taxine alkaloids are found in the plant’s leaves, bark, and seeds. Clinically relevant concentrations of paclitaxel cause multipolar spindle fiber formation causing aneuploidy in mitotic tumor cells (Weaver, 2014). In recent studies, it has been confirmed that chromosomal missegregation and cell death were more likely to happen, when spindle multipolarity lasted longer, especially after anaphase began. However, multipolar spindles caused by paclitaxel throughout mitosis can concentrate into bipolar spindles, and thus cells survive. So, paclitaxel efficacy is expected to be increased by therapies that prevent cells from focusing multipolar spindles caused by paclitaxel into bipolar spindles (Scribano et al., 2021).

When administered with carboplatin, paclitaxel has been used successfully to treat ovarian cancer. A lower concentration of paclitaxel causes apoptosis by upregulating the expression of p21 and p27 genes. At higher concentrations, paclitaxel causes the stable assembly of microtubules from ß tubulin heterodimers and inhibits their depolymerization. Paclitaxel also increases the activity of the enzyme nicotinamide adenine dinucleotide phosphate oxidase; hence, oxidative stress conditions can be enhanced in ovarian cancer cells. In addition to this, multidrug resistance is alarmingly developing in ovarian cancer patients due to altered gene expression, altered tumor microenvironmen, altered cellular metabolism, altered cellular architecture, and altered cellular processes. All these changes cause drug efflux, reduction of intracellular tubulin concentration, and inhibition of mitosis by activating Raf-1 Kinase (Kampan et al., 2015).

After a protracted development period, paclitaxel finally got clinical approval for treatment against resistant breast cancer in 1994 and ovarian cancer in 1992 (Newman et al., 2008). A phase 3 trial of untreated metastatic triple-negative breast cancer patients received atezolizumab plus abraxane or placebo plus abraxane. With atezolizumab plus abraxane, the patients having metastatic triple-negative breast cancer and programmed death ligand 1 (PD-L1) had a more prolonged progression-free survival (Schmid et al., 2018). PD-L1 is an immune response suppressor, and Atezolizumab inhibits PD-L1 function. Hence this combination is a helpful immune-chemotherapy option for patients with PD-L1+ metastatic or locally progressed TNBC (Kang & Syed, 2020). Hematological toxicity is the major drawback of the treatment of gynecological cancer. Recent research studies revealed that the CYP2C8*3 gene variant was significantly linked with severe (grades 3–4) neutropenia and may be used as a potential indicator of hematological toxicities brought on by paclitaxel/carboplatin therapy. Such a predictive assessment might help with the therapeutic intervention of particular individuals receiving chemotherapy based on paclitaxel (de Castro et al., 2019). In another study, the probiotic formulation SLAB51 effectively increased the expression of opioid and cannabinoid receptors in the spinal cord of CIPN mice. Probiotic use also reduces nerve fiber damage in paws (Cuozzo et al., 2021).

MTT assay was performed to access the IC50 value on HER2 positive cancer cell line BT-474, SKBR3. The IC50 values were 19nM and 4 nM for BT-474 and SKBR3 cell lines of breast cancer. Breast cancer cells with positive HER2 receptors have increased expression of oncomiRs. These factors confer resistance to paclitaxel therapy on HER2-positive breast cancer cells (Haghnavaz et al., 2018). Cytotoxicity on 4T1cell line of human breast cancer cells showed the maximum inhibitory concentration IC50 value of 3.78 mM.

Moreover, paclitaxel encapsulated in cyclodextrin nanoparticles increased the bioavailability of paclitaxel (Varan et al., 2021). The maximal inhibitory concentration of paclitaxel in cervical cells cancer cells lines such as HeLa, ME180, CaSki, SiHa, and C33A was found to be 5.39 ± 0.208, 6.59 ± 0.711, 2.940 ± 0.390nM, 19.303 ± 1.886, and 21.567 ± 2.732 nM respectively.

However, paclitaxel-resistant cervical cancer cell lines had increased the PI3K pathway expression. A combination of paclitaxel with PI3K inhibitors such as BYL-719 and LY294002 showed a synergistic effect (J. J. Liu et al., 2019). The IC50 values of paclitaxel and curcumin mixture on the 4T1 cell line and MDA-MB-231 were found to be 4.05 ± 0.13 and 2.79 ± 0.10 mM, respectively. Moreover, the Paclitaxel curcumin nano drug is more efficient than the paclitaxel and curcumin mixture. These nano drugs had better IC50 value than the curcumin and paclitaxel mixture used in triple-negative breast cancer cell lines (Zuo et al., 2021).

Paclitaxel inhibits the function of Bcl-2, a negative apoptosis regulator, in Kaposi’s sarcoma patients (Tourlaki et al., 2020). In treating various carcinomas, Taxol analog docetaxel has gained immense attention. Docetaxel’s therapeutic application is currently constrained because of its non-specific targeted nature and related side effects (Newman et al., 2008). The plant component 10-deacetylbaccatin-III, an inactive precursor chemical found in the needles of the endangered Taxus baccata, is used to synthesize docetaxel artificially (Imran et al., 2020). The low solubility of paclitaxel and docetaxel in water is a significant drawback that results in the low bioavailability of these drugs. Using bio-based nanoparticles such as chitosan helps increase the bioavailability of these drugs (Ashrafizadeh et al., 2020). Many taxol analogs are developed, such as larotaxel dehydrate, paclitaxel polyglumex, cabazitaxel, ortataxel, and taxoperein, are under clinical trials (Newman et al., 2008; Jose, 2020) (Table 1). Phase III clinical trials for treating breast and pancreatic cancer are now being conducted with larotaxel, which features a cyclopropane ring in place of the C-7 hydroxyl group (Newman, Cragg, and Kingston, 2008). It acts on cell lines resistant to paclitaxel and can traverse the blood-brain barrier (Yared and Katherine, 2012). Paclitaxel poliglumex is a nanocarrier for paclitaxel that contains 37% of paclitaxel and is coupled with polyglutamic acid to make it more soluble in water (Newman et al., 2008; Pillai, 2019). A phase III clinical trial using this analog is carried out on ovarian and non-small cell lung cancer patients (Newman et al., 2008). Nanoparticle albumin-bound paclitaxel, DJ-927, Cationic liposomal paclitaxel, polymeric-micelle paclitaxel, DHA-paclitaxel, BMS-184476 are some of the paclitaxel analogs designed to reduce the toxicities mainly neurotoxicity caused by docetaxel and paclitaxel (Newman et al., 2008; Yared and Katherine, 2012).

Structural activity relationship (Supplementary File S2) showed that phenyl moiety at C3′N is necessary for cytotoxicity and antitumor activity. The methoxymethyl group can replace the C7-OH group, and the acetyl group at the C10 position is not necessary for biological activity. Removal of the C2-O-benzyl group reduces biological activity, whereas Ortho and Meta substituted benzyl group increases antitumor activity. Replacement of an eight-member ring with a seven-membered ring can be possible, but an oxetane ring is crucial for compound biological activity (Żwawiak & Zaprutko, 2014)

When the endogenous and exogenous myrosinase hydrolyzes the 4-Methylsulfonylbutyl glucosinolate glucoraphanin, SFN is produced (4-methyl sulfonyl butyl isothiocyanate). The cruciferous vegetables cauliflower, cabbage, mustard, and radish all contain glucosinolates, with broccoli and brussels sprouts having the highest quantities of glucoraphanin (Wang Y. et al., 2016). These glucosinolates are present inactively in plants. At acidic pH, some crucifer plants' epithiospecifier protein (EPS) guides the breakdown of glucoraphanin to produce SFN nitrile. SFN nitrile does not have anti-carcinogenic properties; hence, the downregulation of epithiospecifier protein is necessary to increase sulforaphane production.

Additionally, SFN can be biotransformed reversibly into the erucin metabolite, which affects SFN bioavailability (Bayat Mokhtari et al., 2018). Gut bacteria also possess myrosinase enzyme that converts glucosinolates into isothiocyanate compounds. Gut bacteria in mammals also act on SFN and convert it into an inactive compound (Bayat Mokhtari et al., 2018). Hydrolysis of sinigrin, glucotropaeolin, and gluconasturtiin, glucosinolates leads to the formation of allyl isothiocyanate, benzyl isothiocyanate, and phenyl isothiocyanate, respectively. Upon the action of myrosinase on glucosinolates at basic pH, thiocyanates are formed (Esteve, 2020).

Apoptosis and cell proliferation processes are all regulated by the PI3K-AKT signaling pathway, and in cancer cells, this pathway is predominantly hyperactive (Shi et al., 2019). SFN blocks the function of histone deacetylase, which increases the transcription of genes such as Bax, BAD, and p21 that promote apoptosis. SFE significantly inhibits the PI3K-AKT signaling in lung cancer cells, which results in decreased PTEN expression and reduced phosphorylation of AKT (Yang et al., 2016). SFN can stop CREB from being phosphorylated by MSK2, which inhibits Bcl-2 and further causes apoptosis in esophageal cancer cells (C. Zhang et al., 2019). There have not been many human clinical trials in China that have looked at the effect of SFN on cancer outcomes, but there have been a lot of Phase 1 human SFN investigations using different SFN sources. These investigations are crucial in developing anticancer drugs (Clarke, Dashwood, and Ho 2008).

The action of myrosinase on glucosinolates also leads to the formation of indoles at neutral pH, which, on coming at acidic pH in the stomach, leads to the formation of diindolylmethane (DIM) (Pawlik, Słomińska-Wojewódzka, and Herman-Antosiewicz 2016; Kołodziejski et al., 2019; Koli et al., 2020; Singla et al., 2021; Williams, 2021). DIM in breast cancer cell lines binds to aryl hydrocarbon receptors. This receptor then binds to the Xenobiotic response element sequence in the cytochrome P450 gene family, thereby rendering them transcriptionally active (Esteve, 2020). These cytochromes modify the molecules present within the cells, activating or deactivating them (Ioannides and Lewis, 2005). DIM also affects the activation of the Nrf2 signaling pathway, thereby leading to the production of proteins involved in detoxification and oxidative stress responses (Thomson et al., 2016). In liver cancer cells, DIM suppresses TGF-ß, Smad2/Smad3 signaling, and Ap-1 transcription factor (Wang S. Q. et al., 2016). DIM also regulates the expression of miRNA, which leads to malignancy. In pancreatic cancer cell line, DIM upregulates the expression of let-7b/c/d/e, miR-200b/c, and miR-146a and downregulates the expression of miR-221 miRNA, thereby controlling tumor progression (Biersack, 2020). The combination of calcium ionophore and DIM resulted in increased apoptosis, increased activation of p-p38 MAPK, and cell proliferation was also significantly inhibited in hepatocellular carcinoma cells (Jiang et al., 2019).

Recently synthetic derivatives of DIM, such as 2.2′-diphenyl-3.3′-diindoylmethane (DPDIM) and another halo, phenyl, and ferrocenyl derivatives with anticancer activity, have been developed. Arsindoline B extracted from Xiamen sea bacterium strain CB101 is a natural DIM derivative that shows anticancer activity. Sterptindole extracted from Streptococcus faecium IB 37 is another natural derivative showing DNA-damaging and genotoxic properties (Pillaiyar et al., 2018). DPDIM has anticancer activity on triple-negative breast cancer cells, lacking estrogen receptors, progesterone receptors, and no HER-2 overexpression (Biersack, 2020). IC50 concentration of C-substituted diindolylmethane derivative, namely DIM10 and DIM14 on triple-negative breast cancer cell line MDA-MB-231, MDA-MB-468, and MDA-MB-435 range from 10 to 20 mM after 72 h of treatment. Nano-structured lipid carriers were used to increase the bioavailability of these drugs (Godugu et al., 2016). Although 3.3′diindoylmethane (DIM) is advocated for its efficiency in the treatment of breast and cancer patients, the majority of the prospective trials focused more on the biological fate of DIM than they did on the effectiveness of DIM in the treatment of breast or prostate cancer (Amare, 2020).

Sulforaphane causes cell cycle arrest and inhibits Akt/mTOR pathway and apoptosis in these cells (Yasunaga et al., 2022). Cytotoxicity of Sulforaphane on Estrogen receptor positive cell lines like T47D and MCF-7 cell lines revealed the half-maximum inhibitory concentration of sulforaphane (IC50 value) was 6.6 and 5 mM, respectively. Both erucin and sulforaphane had similar IC50 values of cytotoxicity on these cell lines. However, IC50 values of cytotoxicity by erucin and sulforaphane showed a significant difference on cell line BT-474, with sulforaphane having cytotoxicity at a less inhibitory concentration than erucin. Co-treatment with 4-hydroxytamoxifen, an estrogen inhibitor, and sulforaphane also sensitizes the 4-hydroxytamoxifen-resistant cell line (Pawlik, Słomińska-Wojewódzka, and Herman-Antosiewicz 2016). For MDA-MB-468 TNBC with overexpressing EGFR, the IC50 value of sulforaphane was found to be 1.8 mM.

Parthenolide is found in aerial parts, mainly in leaves of Tanacetum parthenium and Chrysanthemum parthenium. The sesquiterpene lactone family compound 4,5-epoxy-germacra-1 (10),11, (13)-dien-12,6-olide, a secondary metabolite of plants, has three isoprene units and a cyclic ester group (Ghantous et al., 2013). The nucleophilic properties of cyclic ester and epoxide groups enable quick interactions with biological targets. Transcription factor NF-κB is linked to various cellular responses, particularly inflammation, immune regulation, apoptosis, and proliferation. PTL suppresses HDACI-mediated NF-κB activation in acute myeloid leukemia (AML) cells while promoting SAPK/JNK and programmed cell death’s gene activation (Mathema et al., 2012). PTL downregulates the expression of tubulin carboxypeptidase activity; hence, tyrosine ligase can easily tyrosinase tubulins. Healthy neurons and cardiomyocytes have a tubulin detyrosination and retyrosination cycle that regulates microtubule functioning. These highly differentiated cells malfunction when this cycle is dysregulated, and in humans, this can lead to dementia and heart failure (Sanyal et al., 2021). PTL downregulates the expression of DNA methyltransferase enzyme and is less toxic than nucleoside analogs such as 5-azacytidine and decitabine (Ghantous et al., 2013). Additionally, PTL increases ATM gene expression, which decreases the activity of the p21 and histone deacetylase genes. It has been demonstrated that PTL depletes thiols like glutathione (GSH) and blocks related enzymes by alkylation, including GPX1, TXN, TXNRD1/2, and the ligase GCLC1, which accelerates the initial rate-limiting step in the synthesis of GSH. Depletion of glutathione results in the accumulation of ROS and ultimately leads to cell death. PTL also shows anti-proliferative/anti-inflammatory activity. The inhibitory concentration IC50 value for inhibition of COX-2 and TNF-α gene expression by PTL in macrophage cell lines was 0.8 and 0.4 mM, respectively. These genes are involved in inflammatory responses (R. R. A. Freund et al., 2020). Dimethylaminoparthenolide (DMAPT), a PTL analog with improved bioavailability, destroys prostate cancer cells by suppressing NF-κB activity and redox imbalance in the cells (Mendonca et al., 2017) (Table 1). A phase I clinical trial with PTL examined the drug’s pharmacokinetics and toxicity. A phase I clinical trial with DMAPT evaluated cancer patients with acute myeloid leukemia and other blood lymphomas (Sztiller-Sikorska & Czyz, 2020). Dimethylamino-micheliolide fumarate salt (ACT001) is another analog of parthenolide which is under phase I of clinical studies for the treatment of glioma patients. Clinical phase I trials yielded significant findings with acceptable bioavailability and antitumor effectiveness (Sztiller-Sikorska & Czyz, 2020; Lickliter et al., 2021). As PD-L1 gene transcription is decreased by ACT001, the STAT3 pathway, which is overexpressed and contributes to immunosuppression, can also be reduced (Tong et al., 2020).

The structural activity relationship (Supplementary File S3) showed that the C14 methyl group and the presence of lactam moiety are necessary for the antitumor activity of the compound (R. R. A. Freund et al., 2020; J. Long et al., 2016; Jia et al., 2020). Parthenolide derivative with cinnamyl or substituted cinnamyl moiety is effective in triple-negative breast cancer (Ge et al., 2019). Moreover, parthenolide-5-fluorouracil conjugates are also effective against hepatocellular carcinoma (Ding et al., 2019). A lactone ring is necessary for the compound anticancer activity (R. Freund et al., 2019). Through cytotoxicity assay on cell lines SiHa of human cervical cancer cells and breast cancer cell line MCF-7, the IC50 concentration comes out to be 8.42 ± 0.76 and 9.54 ± 0.82 mM, respectively, with p < 0.001. There was over-expression of genes like p53, Bax, caspase6 and caspase3 genes. There was also suppression of expression of the Bcl-2 gene (Al-Fatlawi et al., 2015). The IC50 value of PTL on cancer cell line HCT116 p53+/+ and HCT116 p53−/− of colon carcinoma cells was found to be 17.6 ± 1.8 and 41.6 ± 1.2 mM, respectively. Moreover, the IC50 value for multidrug-sensitive cell lines such as MDA-MB-231-BCRP was found to be 08.5 ± 1.3 mM. This was attributed to the fact that PTL inhibits the NF-κB pathway by binding to IKK and suppressing HIF-1α gene expression (Dawood, Ooko, and Efferth 2019).

Vinca alkaloids from the Catharanthus roseus plant include the naturally occurring bis-indole alkaloids vinblastine and vincristine, as well as various semisynthetic equivalents such as vinorelbine, vinflunine, and KAR-2. Catharanthus roseus yields the alkaloids vinblastine and vincristine, while Vinca minor yields vincamine. Semisynthetic derivatives like vindesine, vinorelbine, and vinflunine are derived from vinblastine and vincristine (Dhyani et al., 2022). Vinblastine, which is primarily used to manage Hodgkin’s disease, and vincristine, which is used in tandem therapy to manage non-lymphoma Hodgkin’s disease, are both now the subject of several human clinical trials (Böll et al., 2011; Škubník et al., 2021). Based on their ability to bind to tubulin, microtubule stabilizing agents can be divided into two groups: those that bind to taxane sites and those that bind to peloruside/laulimalide sites. Vinca domain-binding agents, colchicine domain-binding agents, maytansine site-binding agents, and pironetin site-binding agents are the four categories of microtubule destabilizing agents (Zhang and Kanakkanthara, 2020). Vinca alkaloids inhibit microtubule assembly and cell cycle progression by engaging to α and ß subunits of tubulin (González-Burgos and Gómez-Serranillos 2021). Vinorelbine exhibits neurotoxic effects despite having a stronger affinity for mitotic microtubules than the parent chemical, vincristine. (Milano et al., 2022). Vinblastine and vinorelbine exhibit lower neurotoxicity than vincristine (Verma et al., 2022).

Testicular cancer, Kaposi sarcoma, renal cell carcinoma, lymphoma, and breast and testicular cancer are all treated with vinblastine. One of the main drawbacks of utilizing vinblastine to treat cancer is white blood cell toxicity (Moudi et al., 2013). For non-Hodgkin’s lymphoma, vincristine in combination with medications such as cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone, as well as for Hodgkin’s lymphoma treatment, mechlorethamine, vincristine, procarbazine, and prednisone are used. The most frequent adverse reactions to vincristine are peripheral neuropathy, decreased bone marrow function, constipation, nervous system toxicity, nausea, and vomiting (Moudi et al., 2013). Vincristine-resistant leukemia and lung cancer cells could be treated with vindesine (Dhyani et al., 2022). Although clinical trials are currently being conducted to determine the effects of neuroprotective medicines against vincristine-induced neuropathy, there is currently no proven treatment for CIPN (Islam et al., 2019; Arora & Menezes, 2021). Vincristine, in combination with other drugs, is under clinical trials for intravascular large B-cell lymphoma and peripheral T-cell lymphoma. The phase II clinical study saw positive outcomes for intravascular large B-cell lymphoma (Table 1). However, in phase II clinical trials, severe toxicities were seen for peripheral T-cell lymphoma (Škubník et al., 2021).

Structural activity relationship (Supplementary File S4) showed that the presence of electron-withdrawing groups is essential for the cytotoxic effect of the compound (Hearn, Shaw, and Myles, 2007; Zheng et al., 2013; Mazumder et al., 2022). The cytotoxicity of vinca alkaloids and other chemically synthesized molecules was evaluated. It was found that the IC50 value of these compounds ranges from 0.89 ± 0.07 to 38.22 ± 5.60 mM in the MCF-7 cell line of breast cancer (Table 1). Among all cell lines tested MCF-7 cell line was most sensitive to chemically synthesized simplified vinca alkaloids. These simplified alkaloids inhibited tubulin polymerization (Zheng et al., 2013).

Several bioactive compounds possessing anticancer activity have been extracted from plant sources (Table 1). A phase I clinical trial on 14 patients of prostate cancer by using resveratrol was done for 2–31 months, depending on the patient’s condition. This clinical study increased prostate-specific antigen doubling time (Paller et al., 2015). Similarly, a phase II clinical trial was performed on 24 patients with colorectal cancer by using resveratrol, but this clinical trial resulted in adverse effects on patients (Popat et al., 2013). Besides these clinical trials, poor pharmacokinetics appears to be the two main constraints of the clinical use of resveratrol (Ren et al., 2021). As histone deacetylase inhibitors, sulforaphane, pomiferin, isothiocyanates, and isoflavones stop the activity of proteins that cause cancer (Greenwell & Rahman, 2015). Thymoquinone was tested in a phase I clinical trial on patients with advanced refractory malignant disease in Arabia, and it was shown to be safe and well-tolerated. However, the dosage did not have anticancer efficacy (Al-Amri & Bamosa, 2009). In phase II randomized clinical trial, thymoquinone decreased the oral premalignant lesions (Clinical and Immunohisochemical Evaluation, 2023). Inflammation caused by hepatitis can also lead to hepatocellular carcinoma. Thymoquinone and bee pollen enhanced liver histology in an in vitro rat model of fluvastatin-induced hepatitis (Mohamed et al., 2021). CA-4P (fosbretabulin), a more soluble version of combretastatin-4, exhibited good outcomes in a clinical trial on patients with anaplastic thyroid carcinoma (Mustafa et al., 2022). This water-soluble analog is now in phase II of the clinical trial. Another combretastatin-4 analog, the serine 32 amide AVE8062 (ombrabulin), is undergoing a phase II clinical trial for advanced solid tumors in conjunction with taxanes and platinum salts, as well as a phase II/III clinical trial for patients with advanced soft tissue sarcoma (Zhao et al., 2015).

Based on phase II randomized clinical research, epigallocatechin-3-gallate significantly reduced dermatitis from radiation in breast cancer patients receiving radiotherapy (Zhao et al., 2022). Although several preclinical studies have demonstrated the efficacy of epigallocatechin-3-gallate in the treatment of hepatocellular carcinoma, there is yet to be a clinical trial on actual hepatocellular carcinoma patients (Bimonte et al., 2019). In vitro studies showed that the adverse effects of silver nanoparticles on the therapy of Ehrlich ascetic carcinoma could be reduced by exploiting the antioxidant properties of green tea extracts (Magdy et al., 2020). Clinical trials employing homoharringtonine to treat children with acute refractory myeloid leukemia have been reported; however, these trials were ineffective. However, there were notable outcomes when homoharringtonine was used as an induction treatment along with Ara-C and VP-16 (Chen et al., 2019).

Triptolide also has some potential anticancer efficacy, but its main drawbacks are its limited absorption, low solubility, and toxicity. Moreover, much research has yet to be done on how triptolide affects tumor immune infiltration. Minnelide, an analog of triptolide, is currently under phase II clinical trial to treat advanced pancreatic cancer (Noel et al., 2019). Protopanaxadiol is also under Phase I of a clinical study to treat lung cancer and solid tumors (Asati, 2022). Although bruceantin has been shown to have anticancer action using cell cytotoxicity assay, no clinical trials have been conducted as of yet (Asati, 2022). Roscovitine monotherapy in cancer clinical trials has not been very promising, although clinical trials using RSV and sapacitabine in advanced solid tumors are now being conducted (Pandey et al., 2019).

Curcumin is produced in plants via the phenylpropanoid pathway. Release of NH3 from L-phenylalanine takes place by the enzyme phenylalanine ammonia-lyase, and Trans-cinnamic acid gets formed. Cinnamoate-4-hydroxylase participates in the reaction that transforms trans-cinnamic acid into p-coumaric acid. P-coumaric acid is hydrolyzed by 4-coumarate-3-hydroxylase into caffeic acid. Although the transformation of P-coumaric acid to caffeic acid may not be present in-vivo in Curcuma longa and P-coumaric acid is directly converted to coumaroyl-CoA by the formation of an activated thioester. Caffeoyl-CoA O-methyltransferase enzyme acts on different substrates such as S-adenosyl-L-methionine and caffeoyl-CoA. The end product of these catalytic reactions is S-adenosyl-L-homocysteine and feruloyl-CoA, respectively. Diketide-CoA is hydrolyzed into the equivalent ß-keto acid by the enzyme diketide-CoA synthase (Figure 2). ß- Ketoacid then gets condensed with feruloyl-CoA by the enzyme curcumin synthase and curcumin forms. Horinouchi and colleagues first reported the enzyme curcumin synthase. The enzyme curcumin synthase couples two molecules of coumaryl-CoA and one malonyl-CoA from the plant Oryza sativa to form bisdemethoxycurcumin. Curcumin synthase also catalyzes the reaction of conversion of ß-Keto acid and coumaryl-CoA to form Bisdemethoxycurcumin (Rodrigues et al., 2015). Different metabolic engineering strategies such as deletion of poxB, curA, and adhE genes, overexpression of acs gene, and inactivation of the fabF gene have helped improve curcumin’s biosynthesis in a heterologous system (Wu et al., 2020).

The Biosynthesis of Epipodophyllotoxin takes place through the phenylpropanoid pathway. Both phenylalanine and cinnamic acid are stable precursors for podophyllotoxin biosynthesis (Shah et al., 2021). Phenylalanine deamination takes place with the help of the enzyme phenylalanine ammonia-lyase to form cinnamic acid—a multi-step enzymatic process, including hydroxylation, methyl transfer, reduction, and dehydrogenation from coniferyl alcohol. Two molecules of coniferyl alcohol are combined to form pinoresinol by the enzyme dirigent protein oxidase (Figure 3). From pinoresinol, biosynthesis of diverse lignans takes place through various enzymatic steps. For the synthesis of epipodophyllotoxin, pinoresinol is subsequently reduced and dehydrogenated by enzymes pinoresinol, lariciresinol reductase, and secoisolariciresinol dehydrogenase to form matairesinol. Deoxypodophyllotoxin is hydroxylated to either podophyllotoxin or ß peltatin by the enzymes deoxypodophyllotoxin-7-hydroxylase and deoxypodophyllotoxin-6-hydroxylase, respectively (Yousefzadi et al., 2010). The steps that lead to the formation of deoxypodophyllotoxin are not clear.

In plastids, through the methylerythritol phosphate pathway, pyruvate and D-glyceraldehyde 3-phosphate react in multistep enzymatic steps to form isopentenyl pyrophosphate and dimethylallyl pyrophosphate. There is the condensation of three isopentenyl pyrophosphate molecules with one molecule of dimethylallyl pyrophosphate. However, the cytosolic mevalonate pathway also generates precursors such as isopentenyl pyrophosphate and dimethylallyl pyrophosphate, and the formation of paclitaxel can be stopped by inhibitors of both processes (Malik et al., 2011). The cyclization of geranylgeranyl diphosphate (GGPP) to taxa-4 (5), 11 (12) diene4 (taxadiene) is catalyzed by taxadiene synthase, and it marks the beginning of the taxol biosynthesis process. The tricyclic structure formed then goes through several oxygenations and acylations reactions that are region-specific and stereo-specific, carried out by different cytochrome P450 (cP450) oxygenases and acyltransferases. Membrane-bound plant cytochrome P450 called taxadiene-5-Hydroxylase, catalyzes the conversion of taxadiene to taxadiene-5α-ol (Figure 4). Then taxadiene-13α-hydroxylase leads to the conversion of taxadiene-5α-ol to Taxadien-5α -13 α-diol. Through a series of unidentified steps, Taxadien-5α -13 α-diol is converted to 2-Debenzoyltaxane. Hydroxylation reaction converts 2-Debenzoyltaxane to 10- Deacylbaccatin III.

ß-PhenylalanineCoA and Baccatin III in the presence of enzyme baccatin III-13-Ophenylpropanoyl transferase mediate the attachment of ß-PhenylalanineCoA to taxane core. Further acetylation at the C10 position produces Baccatin III, and this reaction is catalyzed by 10-deacetylbaccatin III-10-Oacetyltransferse. By hydroxylation of ß-Phenylalanoyl baccatin III through an unknown c450 enzyme, there is the formation of N-Debenzoyltaxol. The transfer of the benzoyl group to core taxane by enzyme 3′ –N-dibenzoyl-2′ –deoxytaxol-N-benzoyl transferase leads to the formation of the final product paclitaxel (Phillips et al., 2008; Howat et al., 2014; McElroy & Jennewein, 2018; Göbel et al., 2020).

Glucoraphanin acts as a precursor for the biosynthesis of sulforaphane. In the biosynthetic pathway, there are steps where elongation of the methionine side chain takes place, and other steps include the formation of glucosinolate and side chain modifications of glucosinolate (Supplementary File S5). Through multi-enzymatic steps, methionine gets converted into glucosinolate glucoraphanin. When a plant is injured, the enzyme ß-thioglucosidase, a myrosinase, comes into contact with the glucoraphanin and hydrolyzes it to create the unstable aglucone, which is easily transformed into the isothiocyanate sulforaphane (Supplementary File S6). Core significations in sulforaphane structure also take place through different enzymes in plants. The conversion of methionine to homomethionine takes place in the chloroplast. Flavin monooxygenase converts 4-methylglucosinolate into glucoraphanin (Yagishita et al., 2019; Z. Li et al., 2019; Janczewski, 2022; Nguyen et al., 2020; Neal et al., 2010).

The glandular trichomes in feverfew plant flowers contain an excessive amount of parthenolide, and its biosynthesis takes place, presumably by the mevalonate pathway. However, the compounds produced in a heterologous system were conjugated parthenolide (Q. Liu et al., 2014). In the mevalonate pathway, Farnesyl pyrophosphate is formed when two molecules of isopentenyl pyrophosphate and one molecule of dimethylallylpyrophosphate react in the presence of Farnesyl pyrophosphate synthase enzyme. Dimethylallylpyrophosphate can be reversibly changed into isopentenyl pyrophosphate by the enzyme isopentenyl diphosphate isomerase. Germarcene A is formed first, then germacrene A oxidase and Cytochrome P450 work together in a multi-step process to produce germacranoic acid (Figure 5). From costunolide final synthesis of Parthenolide takes place (Majdi et al., 2011; Agabiti et al., 2017). Identification of essential genes involved in the biosynthesis of parthenolide in feverfew plants, such as parthenolide synthase (TpPT), germacrene A synthase (TpGAS), germacrene A oxidase (TpGAO) and costunolide synthase (TpCOS) had helped in heterologous expression of parthenolide in Nicotiana benthamiana through metabolic engineering strategies.

The multistep enzymatic process of tryptamine production from chorismate involves the shikimic acid pathway. Anthranilate synthase catalyzes the transfer of the amido group from glutamine in a two-step process to form anthranilate. The formation of pyruvate and glutamate takes place during this reaction. Anthranilate phosphoribosyl anthranilate transferase catalyzes the transformation of anthranilate to 5-phosphoribosyl anthranilate by the transfer of the 5-phosphoribosephosphate group. Through a series of enzymatic steps, there is the formation of indole glycerol phosphate takes place. Both α and ß subunits of the tryptophan synthase enzyme participate in the formation of tryptophan. The tryptophan synthase α subunit catalyzes the formation of the indole ring, and the tryptophan synthase ß subunit adds serine residue to the indole ring, thus forming tryptophan. Tryptophan decarboxylase is an enzyme involved in the decarboxylation reaction that produces tryptamine (Supplementary File S7). Both Mevalonate and Methylerythritol phosphate pathways through multistep enzymatic steps can lead to the formation of geranyl pyrophosphate. This geranyl pyrophosphate is converted to geraniol by the enzyme geraniol synthase. NADPH: cytochrome P450 reductase then acts on geraniol to form 10- hydroxygeraniol. Secologanin is synthesized through a multistep enzymatic process mediated by many cytochrome P450 monooxygenase enzymes, including geraniol 10-hydroxylase, deoxyloganin 7-hydroxylase, and secologanin synthase. When the enzyme strictosidine synthase is present, the reactions between tryptophan and secologanin produce strictosidine during strictosidine biosynthesis (Supplementary File S7). Different terpenoid indole alkaloids can be produced using strictosidine as a precursor. Crystallization of strictosidine produces strictosamide. Further oxidation-recyclization reactions lead to the formation of camptothecin (Sirikantaramas, Yamazaki, and Saito 2013).

Additionally, vinblastine and vindoline are biosynthesized with strictosidine as a precursor. Through hydroxylation and acetyltransferase reactions, the formation of vindoline takes place. Vindoline and catharanthine through acetyltransferase reaction catalyzed by enzyme Deacetylvindoline 4-O-acetyl transferase lead to the formation of vinblastine. The product of vindoline and Catharine coupling is α3′4′anhydrovinblastine, and further, this product is converted into vinblastine (Supplementary File S8). This vinblastine is further converted to vincristine through an unknown enzyme (Sirikantaramas, Yamazaki, and Saito, 2013; Zhu et al., 2015). The enzyme involved in this process is unknown.