J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

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Review

Volume 17, Number 8, August 2025, pages 423-436

Prevention of Chromium-Induced Radiation-Chemical Oncogenesis, Including in Offspring, in an Experimental Model: A Systematic Review

Figure 1. Flow chart for the systematic literature review on the prevention of radiation- and chemical-induced oncogenesis. Source: authors’ development in accordance with PRISMA 2020 recommendations. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; ROS: reactive oxygen species.

Figure 2. Mechanism for the prevention of radiation-induced oncogenesis using phytopreparations. Source: authors’ development.

**Table 1.** Mechanism of Radiation and Chromium-Induced Oncogenesis
Mechanism	Developmental process
IR: ionizing radiation; ncRNA: non-coding RNAs; DSBs: DNA double-strand breaks; Cr: chromium; H₂O₂: hydrogen peroxide; OH: hydroxyl radical; ROS: reactive oxygen species; UVB: ultraviolet B radiation; UVA: ultraviolet B radiation; UVC: ultraviolet C radiation.
Mutations in DNA	IR can cause all forms of mutations [17]. Mutation in DNA occurs following alterations in the nucleotide sequence that make up DNA strand, which can result from environmental changes such as chemicals or UV rays and random mistakes in DNA replication [18, 19]. UV and IR induce a qualitatively similar spectrum of DNA lesions, including base alterations, base loss, inter- and intra-strand crosslinks, DNA-protein cross links, regions of denaturation, alkali-labile sites, single-strand breaks and double-strand breaks in the deoxyribose phosphodiester backbone [20], as well as clustered DNA lesions [21]. UVA and UVB radiations lead to the excitation of endogenous sensitizing molecules which produce singlet oxygen and oxidative radicals in the presence of oxygen that results in DNA damage. UVC radiation results in direct excitation and subsequent alteration of the purine and pyrimidine rings [20, 22-24].
	IR mostly targets DNA [25]. Direct exposure to this form of radiation results in DNA lesion including single- and double-strand breaks [25, 26]. Indirect exposure to IR splits water molecules near DNA, creating hydrogen and hydroxyl free radicals; which can be converted to ROS, OH, H₂O₂, etc. [4, 27, 28]; the hydroxyl free radical may react with nearby DNA, producing single-strand DNA breaks, which may spontaneously be converted into a double-strand break. Radiation-induced double-strand breaks is considered the most lethal form of DNA damage [26, 29]. The processing and repair of DSBs can result in mutations, as well as chromosome rearrangements, consequently leading to apoptosis or cancer [30]. Exposure to Cr (IV)-containing compounds has also been reported to produce DNA strand breaks, as well as chromosomal abnormalities and genomic instability which is associated with the development of human lung cancer [31, 32].
Epigenetic modifications resulting from non-mutations-based changes in gene expressions	DNA methylation, modification in histones and ncRNAs are all incidents in the development of radiation induced cancer.
DNA methylation	DNA methylation, which is the covalent addition of methyl groups to the DNA fosters gene regulation as such hypermethylation of genomic DNA is linked to gene silencing, while hypomethylation of the DNA is linked to chromosomal instability [33, 34], and a reduction in DNA methylation levels caused by IR results in an increase in DNA strand breaks and enhanced recombination activity [35]. Therefore, the loss of DNA methylation in specific regions of the eukaryotic genome (such as in the non-coding repetitive elements: transposable elements) may result in genomic instability which is considered a primary hallmark of a host of cancers [33, 34].
Histone modification	Histones, structural proteins that control the dynamism of chromatin, thus making gene regulation at all stages of development in higher organisms achievable [36], are made up of several amino acid residues, which when modified affect the structure of chromatin, consequently, alter transcriptional responses [37], as well as all processes that require access to the DNA [38]. Histone modification occurs mainly by acetylation and methylation [39]; changes in histone acetylation levels have been attributed to the occurrence of some tumors via the downregulation of some tumor suppressor genes, and overexpression of the enzymes involved in histone methylation has been shown to spur the progression of various oncogenes [29].
ncRNA	ncRNAs play important roles in disease development including cancers and IR-induced damage. This is because they are involved in the regulation of cellular processes and cellular stress response [29]. Several studies have provided evidence that ncRNAs play an important role in regulating cancer metabolic reprogramming (abnormal metabolism of glucose, amino acids and lipids found in cancerous cells and tissues); this altered metabolic networks mediated by ncRNAs promote carcinogenesis by controlling the expression of metabolic enzymes and transporter proteins via dysregulation in various metabolic signaling pathways [25].

Table 1. Mechanism of Radiation and Chromium-Induced Oncogenesis

Mechanism

Developmental process

IR: ionizing radiation; ncRNA: non-coding RNAs; DSBs: DNA double-strand breaks; Cr: chromium; H₂O₂: hydrogen peroxide; OH: hydroxyl radical; ROS: reactive oxygen species; UVB: ultraviolet B radiation; UVA: ultraviolet B radiation; UVC: ultraviolet C radiation.

Mutations in DNA

IR can cause all forms of mutations [17]. Mutation in DNA occurs following alterations in the nucleotide sequence that make up DNA strand, which can result from environmental changes such as chemicals or UV rays and random mistakes in DNA replication [18, 19]. UV and IR induce a qualitatively similar spectrum of DNA lesions, including base alterations, base loss, inter- and intra-strand crosslinks, DNA-protein cross links, regions of denaturation, alkali-labile sites, single-strand breaks and double-strand breaks in the deoxyribose phosphodiester backbone [20], as well as clustered DNA lesions [21]. UVA and UVB radiations lead to the excitation of endogenous sensitizing molecules which produce singlet oxygen and oxidative radicals in the presence of oxygen that results in DNA damage. UVC radiation results in direct excitation and subsequent alteration of the purine and pyrimidine rings [20, 22-24].

IR mostly targets DNA [25]. Direct exposure to this form of radiation results in DNA lesion including single- and double-strand breaks [25, 26]. Indirect exposure to IR splits water molecules near DNA, creating hydrogen and hydroxyl free radicals; which can be converted to ROS, OH, H₂O₂, etc. [4, 27, 28]; the hydroxyl free radical may react with nearby DNA, producing single-strand DNA breaks, which may spontaneously be converted into a double-strand break. Radiation-induced double-strand breaks is considered the most lethal form of DNA damage [26, 29]. The processing and repair of DSBs can result in mutations, as well as chromosome rearrangements, consequently leading to apoptosis or cancer [30]. Exposure to Cr (IV)-containing compounds has also been reported to produce DNA strand breaks, as well as chromosomal abnormalities and genomic instability which is associated with the development of human lung cancer [31, 32].

Epigenetic modifications resulting from non-mutations-based changes in gene expressions

DNA methylation, modification in histones and ncRNAs are all incidents in the development of radiation induced cancer.

DNA methylation

DNA methylation, which is the covalent addition of methyl groups to the DNA fosters gene regulation as such hypermethylation of genomic DNA is linked to gene silencing, while hypomethylation of the DNA is linked to chromosomal instability [33, 34], and a reduction in DNA methylation levels caused by IR results in an increase in DNA strand breaks and enhanced recombination activity [35]. Therefore, the loss of DNA methylation in specific regions of the eukaryotic genome (such as in the non-coding repetitive elements: transposable elements) may result in genomic instability which is considered a primary hallmark of a host of cancers [33, 34].

Histone modification

Histones, structural proteins that control the dynamism of chromatin, thus making gene regulation at all stages of development in higher organisms achievable [36], are made up of several amino acid residues, which when modified affect the structure of chromatin, consequently, alter transcriptional responses [37], as well as all processes that require access to the DNA [38]. Histone modification occurs mainly by acetylation and methylation [39]; changes in histone acetylation levels have been attributed to the occurrence of some tumors via the downregulation of some tumor suppressor genes, and overexpression of the enzymes involved in histone methylation has been shown to spur the progression of various oncogenes [29].

ncRNA

ncRNAs play important roles in disease development including cancers and IR-induced damage. This is because they are involved in the regulation of cellular processes and cellular stress response [29]. Several studies have provided evidence that ncRNAs play an important role in regulating cancer metabolic reprogramming (abnormal metabolism of glucose, amino acids and lipids found in cancerous cells and tissues); this altered metabolic networks mediated by ncRNAs promote carcinogenesis by controlling the expression of metabolic enzymes and transporter proteins via dysregulation in various metabolic signaling pathways [25].

**Table 2.** Overview of the Included Research Articles
Reference	Type of exposure	Phytopreparation	Summary of paper
A. linearis: Aspalathus linearis; C. trichotomum: Clerodendrum trichotomum; CTE: C. trichotomum extract; ATP: adenosine triphosphate; H&E: hematoxylin and eosin; ATP: adenosine triphosphate; E: erythema score; FA: ferulic acid; IL: interleukin; MDA: malonic dialdehyde; MMP: matrix metalloproteinase; NF-κB: nuclear factor kappa; NRS: numerical rating scale; ROS: reactive oxygen species; SKMEL-1: skin melanoma cell line 1; TAC: total antioxidant capacity; TNF-α: tumor necrosis factor alpha; TOS: total oxidative status; TXB2: thromboxane B2; U: ulceration score; UVB: ultraviolet B radiation; MAPK: mitogen-activated protein kinase; WHO: World Health Organization.
[56]	Gamma-radiation and chromium (IV)	Burdock root oil	Adult male and female rats were exposed to gamma irradiation, hexavalent chromium, and a combination of the two treatments. Prior to exposure, the subjects were treated with burdock root oil. Afterwards the male and female subjects were crossbreed (1:1) to obtain first-generation offsprings which later served as the major participants of the research. A positive control group containing similar subjects without exposure to either treatment and two negative controls; subjects exposed to gamma radiation only and those exposed to gamma radiation and chromium (IV) were also set up. The genotoxicity of exposure to offsprings was studied using samples from the bone marrow cells, chromosomal aberration was observed to be pronounced in the offsprings exposed to both gamma irradiation and chromium (IV) than in either of these agents alone, and it was also observed that the offsprings of parents who received treatment prior to exposure to both agents had significant improvements in chromosome integrity, while those treated with burdock root oil and received exposure to either form of the agent had chromosome integrity similar to the positive control group. A 16% decrease in the MDA levels was observed in the group exposed to both agents which was comparable to the levels of MDA observed in the positive control group. Cytokine profile analysis revealed a 43% and 40% increase in the pro-inflammatory cytokines, IL-6 and TNF-α respectively while the level of anti-inflammatory cytokines decreased by 21% compared to the positive control, a strong indication of an imbalance in pro- and anti-inflammatory cytokines. However, offsprings from parents that received treatment prior to exposure had IL-10 levels similar to that of the positive control and reduced values of pro-inflammatory cytokines. The study highlighted the anti-oxidative and anti-genotoxic effect of burdock root oil on genotoxicants transferred from parents to offsprings.
[57]	Gamma radiation	Umbelliferon (7-hydroxycoumarin)	To determine the impact of umbelliferon on radiation-induced cardiac damages, male rats were exposed to 12 Gy of gamma irradiation and treated with umbelliferon (25, 50, 100 kg/mg body weight per day) prior to exposure. A negative control without treatment with umbelliferon received the same dose of gamma irradiation, while two positive controls included subjects that received physiological saline alone and umbelliferon. Biochemical parameters including TAC and TOS, as well as TNF-α, TXB2 were evaluated using samples collected from heart tissues. In the group exposed to radiation without treatment, the TOS levels increased by approximately 23% and the TAC reduced by 34%, indicative of oxidative imbalance in the heart tissue. This was, however, not observed in the group treated with umbelliferone prior to exposure It was further observed that the group treated with 100 kg/mg umbelliferone had TOS and TAC values comparable to the positive control group that received physiological saline. This same group was observed to have reduced levels of inflammatory activity as determined by measuring the TNF-α values. Compared to other groups, the value of TXB2 in the irradiated group was significantly elevated, which was indicative of vascular injury; however, the value of TXB2 in the treated group was similar with that of the positive control group, which received physiological saline. Histological examination showed significant damage in the irradiated group, which was not observed in the group that received treatment before exposure to radiation.
[58]	UVB	Acetone extract of green A. linearis	Human epidermal keratinocytes (HaCaT) and melanoma (SKMEL-1) cells were exposed to UVB radiation. Prior to exposure, the cells were cultured in Roswell Park Memorial Institute medium and treated for 4 and 24 h with various concentration (0, 10, IC₅₀ and100 µ/mL) of A. linearis). It was discovered that the cytotoxic effect of UVB on cells were both time-and dose-dependent, with the treated cells showing more viability even at low concentration of treatment dosage than the UVB-exposed cells without treatment, indicating the protective activity of the phytopreparation. Further, cell viability was examined using ATP bioluminescence assay, lowest concentration of all treatment significantly increased ATP levels in the HaCat cells after 4 h of exposure to UVB. A similar observation was reported in the SKMEL-1 cells, which was comparable to that of the control. Caspase 3 activity (indicative of apoptosis) was also reduced by the lowest concentration of the phytopreparation. The cytoprotective activity of A. linearis was associated with the presence of linearitin, aspalathin and nothofagin in this phytopreparation, with linearitin having more pronounced effect than the other compounds.
[59]	X-rays	Ferulic acid (FA)	Human lens epithelial cells were exposed to 4 Gy of X-ray. Prior to exposure, the cells were pretreated with FA for 2 h, the positive controls were exposed to sham radiation while negative control were exposed to radiation without any treatment; and all samples were incubated for 72 h. Afterwards, cells were observed under the phase contrast microscope. In negative control, the cells were swollen and disorderly arranged, which was not the case with the pretreated sample as cell morphology was significantly improved. Apoptosis induced by exposure to radiation was analyzed by flow cytometry; it was observed that FA-pretreated cells were resistant to apoptosis in a dose-dependent manner. Further, proteins involved in apoptotic process were quantified; the expression of the Bcl-2 protein (which regulates apoptosis) was significantly increased, while those of the cleaved/procaspase-3 (fosters apoptosis) were downregulated. ROS and MDA values were also significantly reduced in the pretreated cells. The molecular mechanism of the antioxidant prowess of the phytopreparation was assessed by examining the impact of the phytopreparation on the Nrf2 (genes concerned with the oxidative defense in the eye lens) signaling pathway and its downstream genes. A significant increase in the nuclear Nrf2 and decrease in cytosolic Nrf2 were observed, indicating the efficacy of this agent to stimulate specific pathways capable of releasing products that annihilate oxidative stress induced by irradiation on the lens cells.
[60]	UVB	CTE	Adult male HR-1 hairless mice were exposed to UVB irradiation for 12-week period, thrice weekly, treatment with CTE was administered simultaneously daily (five times a week). A positive control group and a negative control group were also set up. H&E staining revealed CTE’s protective effect on the treated cells against UVB-induced epidermal alterations and increased collagen fiber abundance were observed following Masson’s trichome staining. Continuous UVB exposure for 12 weeks resulted in elevation in the levels of MMP associated with UVB-induced skin damage in the skin tissues of mice exposed to irradiation without treatment. CTE administration effectively reduced the levels of MMP, and this effect was attributed to the notable increase in the phosphorylation levels of MAPK signaling pathway, which modulated the expression of MMP. The protective effect of this phytopreparation on UVB-induced skin photoaging was associated with the presence of acteoside, isoacteoside, among other compounds (martynoside, and isomartynoside) present in this agent.
[61]	UVB	Ursolic acid (UA)	Human skin dermal fibroblast cells were exposed to UVB of 40 mJ/cm² for 30 min, with the test group comprising cells treated with 10, 20 and 40 µM UA as well as cells prior to irradiated. A negative control and a positive control group were also set up. Fluorescence microscopy shows the presence of dense staining, indicative of pronounced levels of intracellular ROS in the cells exposed to UVB without treatment, which was not the case with either of the positive control and the cells pretreated with 20 µM UA, suggesting the ROS scavenging capacity of this agent; the same concentration of UA also showed maximum protection against UVB-induced oxidative lipid peroxidation compared to other concentrations. Cells pretreated with 20 µM without exposure to UVB showed no damage to DNA, increased ROS or TNF-α and NF-κB (concerned with cytokine production) levels, which were comparable with cells neither pretreated nor exposed to radiation sources.
[62]	Radiation/chemotherapy for 6 - 7 weeks	Curcumin mouth wash	Adult cancer patients who had undergone radiotherapy and with signs of oral mucositis were grouped into a test and a control group. The control group received chlorohexidine mouth wash, and the test group was treated with curcumin mouthwash each, 3 times daily. Both the standard mouthwash and curcumin were administered for 20 days. The patients were exposed to 65 - 70 Gy of radiation and subsequent treatment with chemotherapy. Erythema and ulceration were recorded using the NRS, E, U and WHO Oral Mucositis Assessment Scale (OMAS). A statistically significant result was reported between the baseline score and the second follow-up score for all scales between the study and control group, indicating the efficacy of curcumin and with no reports on adverse effects in the group that treated with curcumin mouthwash.

Table 2. Overview of the Included Research Articles

Reference

Type of exposure

Phytopreparation

Summary of paper

A. linearis: Aspalathus linearis; C. trichotomum: Clerodendrum trichotomum; CTE: C. trichotomum extract; ATP: adenosine triphosphate; H&E: hematoxylin and eosin; ATP: adenosine triphosphate; E: erythema score; FA: ferulic acid; IL: interleukin; MDA: malonic dialdehyde; MMP: matrix metalloproteinase; NF-κB: nuclear factor kappa; NRS: numerical rating scale; ROS: reactive oxygen species; SKMEL-1: skin melanoma cell line 1; TAC: total antioxidant capacity; TNF-α: tumor necrosis factor alpha; TOS: total oxidative status; TXB2: thromboxane B2; U: ulceration score; UVB: ultraviolet B radiation; MAPK: mitogen-activated protein kinase; WHO: World Health Organization.

[56]

Gamma-radiation and chromium (IV)

Burdock root oil

Adult male and female rats were exposed to gamma irradiation, hexavalent chromium, and a combination of the two treatments. Prior to exposure, the subjects were treated with burdock root oil. Afterwards the male and female subjects were crossbreed (1:1) to obtain first-generation offsprings which later served as the major participants of the research. A positive control group containing similar subjects without exposure to either treatment and two negative controls; subjects exposed to gamma radiation only and those exposed to gamma radiation and chromium (IV) were also set up. The genotoxicity of exposure to offsprings was studied using samples from the bone marrow cells, chromosomal aberration was observed to be pronounced in the offsprings exposed to both gamma irradiation and chromium (IV) than in either of these agents alone, and it was also observed that the offsprings of parents who received treatment prior to exposure to both agents had significant improvements in chromosome integrity, while those treated with burdock root oil and received exposure to either form of the agent had chromosome integrity similar to the positive control group. A 16% decrease in the MDA levels was observed in the group exposed to both agents which was comparable to the levels of MDA observed in the positive control group. Cytokine profile analysis revealed a 43% and 40% increase in the pro-inflammatory cytokines, IL-6 and TNF-α respectively while the level of anti-inflammatory cytokines decreased by 21% compared to the positive control, a strong indication of an imbalance in pro- and anti-inflammatory cytokines. However, offsprings from parents that received treatment prior to exposure had IL-10 levels similar to that of the positive control and reduced values of pro-inflammatory cytokines. The study highlighted the anti-oxidative and anti-genotoxic effect of burdock root oil on genotoxicants transferred from parents to offsprings.

[57]

Gamma radiation

Umbelliferon (7-hydroxycoumarin)

To determine the impact of umbelliferon on radiation-induced cardiac damages, male rats were exposed to 12 Gy of gamma irradiation and treated with umbelliferon (25, 50, 100 kg/mg body weight per day) prior to exposure. A negative control without treatment with umbelliferon received the same dose of gamma irradiation, while two positive controls included subjects that received physiological saline alone and umbelliferon. Biochemical parameters including TAC and TOS, as well as TNF-α, TXB2 were evaluated using samples collected from heart tissues. In the group exposed to radiation without treatment, the TOS levels increased by approximately 23% and the TAC reduced by 34%, indicative of oxidative imbalance in the heart tissue. This was, however, not observed in the group treated with umbelliferone prior to exposure It was further observed that the group treated with 100 kg/mg umbelliferone had TOS and TAC values comparable to the positive control group that received physiological saline. This same group was observed to have reduced levels of inflammatory activity as determined by measuring the TNF-α values. Compared to other groups, the value of TXB2 in the irradiated group was significantly elevated, which was indicative of vascular injury; however, the value of TXB2 in the treated group was similar with that of the positive control group, which received physiological saline. Histological examination showed significant damage in the irradiated group, which was not observed in the group that received treatment before exposure to radiation.

[58]

UVB

Acetone extract of green A. linearis

Human epidermal keratinocytes (HaCaT) and melanoma (SKMEL-1) cells were exposed to UVB radiation. Prior to exposure, the cells were cultured in Roswell Park Memorial Institute medium and treated for 4 and 24 h with various concentration (0, 10, IC₅₀ and100 µ/mL) of A. linearis). It was discovered that the cytotoxic effect of UVB on cells were both time-and dose-dependent, with the treated cells showing more viability even at low concentration of treatment dosage than the UVB-exposed cells without treatment, indicating the protective activity of the phytopreparation. Further, cell viability was examined using ATP bioluminescence assay, lowest concentration of all treatment significantly increased ATP levels in the HaCat cells after 4 h of exposure to UVB. A similar observation was reported in the SKMEL-1 cells, which was comparable to that of the control. Caspase 3 activity (indicative of apoptosis) was also reduced by the lowest concentration of the phytopreparation. The cytoprotective activity of A. linearis was associated with the presence of linearitin, aspalathin and nothofagin in this phytopreparation, with linearitin having more pronounced effect than the other compounds.

[59]

X-rays

Ferulic acid (FA)

Human lens epithelial cells were exposed to 4 Gy of X-ray. Prior to exposure, the cells were pretreated with FA for 2 h, the positive controls were exposed to sham radiation while negative control were exposed to radiation without any treatment; and all samples were incubated for 72 h. Afterwards, cells were observed under the phase contrast microscope. In negative control, the cells were swollen and disorderly arranged, which was not the case with the pretreated sample as cell morphology was significantly improved. Apoptosis induced by exposure to radiation was analyzed by flow cytometry; it was observed that FA-pretreated cells were resistant to apoptosis in a dose-dependent manner. Further, proteins involved in apoptotic process were quantified; the expression of the Bcl-2 protein (which regulates apoptosis) was significantly increased, while those of the cleaved/procaspase-3 (fosters apoptosis) were downregulated. ROS and MDA values were also significantly reduced in the pretreated cells. The molecular mechanism of the antioxidant prowess of the phytopreparation was assessed by examining the impact of the phytopreparation on the Nrf2 (genes concerned with the oxidative defense in the eye lens) signaling pathway and its downstream genes. A significant increase in the nuclear Nrf2 and decrease in cytosolic Nrf2 were observed, indicating the efficacy of this agent to stimulate specific pathways capable of releasing products that annihilate oxidative stress induced by irradiation on the lens cells.

[60]

UVB

CTE

Adult male HR-1 hairless mice were exposed to UVB irradiation for 12-week period, thrice weekly, treatment with CTE was administered simultaneously daily (five times a week). A positive control group and a negative control group were also set up. H&E staining revealed CTE’s protective effect on the treated cells against UVB-induced epidermal alterations and increased collagen fiber abundance were observed following Masson’s trichome staining. Continuous UVB exposure for 12 weeks resulted in elevation in the levels of MMP associated with UVB-induced skin damage in the skin tissues of mice exposed to irradiation without treatment. CTE administration effectively reduced the levels of MMP, and this effect was attributed to the notable increase in the phosphorylation levels of MAPK signaling pathway, which modulated the expression of MMP. The protective effect of this phytopreparation on UVB-induced skin photoaging was associated with the presence of acteoside, isoacteoside, among other compounds (martynoside, and isomartynoside) present in this agent.

[61]

UVB

Ursolic acid (UA)

Human skin dermal fibroblast cells were exposed to UVB of 40 mJ/cm² for 30 min, with the test group comprising cells treated with 10, 20 and 40 µM UA as well as cells prior to irradiated. A negative control and a positive control group were also set up. Fluorescence microscopy shows the presence of dense staining, indicative of pronounced levels of intracellular ROS in the cells exposed to UVB without treatment, which was not the case with either of the positive control and the cells pretreated with 20 µM UA, suggesting the ROS scavenging capacity of this agent; the same concentration of UA also showed maximum protection against UVB-induced oxidative lipid peroxidation compared to other concentrations. Cells pretreated with 20 µM without exposure to UVB showed no damage to DNA, increased ROS or TNF-α and NF-κB (concerned with cytokine production) levels, which were comparable with cells neither pretreated nor exposed to radiation sources.

[62]

Radiation/chemotherapy for 6 - 7 weeks

Curcumin mouth wash

Adult cancer patients who had undergone radiotherapy and with signs of oral mucositis were grouped into a test and a control group. The control group received chlorohexidine mouth wash, and the test group was treated with curcumin mouthwash each, 3 times daily. Both the standard mouthwash and curcumin were administered for 20 days. The patients were exposed to 65 - 70 Gy of radiation and subsequent treatment with chemotherapy. Erythema and ulceration were recorded using the NRS, E, U and WHO Oral Mucositis Assessment Scale (OMAS). A statistically significant result was reported between the baseline score and the second follow-up score for all scales between the study and control group, indicating the efficacy of curcumin and with no reports on adverse effects in the group that treated with curcumin mouthwash.

**Table 3.** Major Phytoconstituents With Anti-Cancer Properties and Their Mechanism of Activity
Phytochemicals	Mechanism of anti-cancer activity
ROS: reactive oxygen species.
Flavonoids and phenolic compounds	The flavonoid structure’s numerous hydroxy groups, combined with a highly conjugated electron system, allow them to act as a free radical scavenger via hydrogen atom or electron-donating activities. They can also inhibit the formation of ROS and act as pro-oxidative compounds [82, 83]. phenolic compounds also exert their preventive role though cell cycle arrest, apoptosis, and most importantly, scavenging free radicals responsible for carcinogenesis and its progression [51, 84-86].
Alkaloids	Alkaloids are a group of ring structure nitrogen containing organic compounds with a wide range of anti-cancer activity [87]. These compounds take part in cancer inhibition via prevention of enzyme topoisomerase activity which is involved in DNA imitation, inducing apoptosis and expression of p53 gene [88-90]. Further, some groups (indole, pyrrole, isoquinoline, etc.) of alkaloids have been reported to exhibit cytotoxic activities against various cancer cell lines by inducing autophagy, necroptosis and apoptosis under the influence of various proteins involved in the apoptotic pathway [91].
Tannins	Inhibition of proliferation of cancerous cells by downregulating the expression of anti-inflammatory enzymes, anti-apoptotic proteins and regulation of specific pathways responsible for tumor cell migration as well as induction of cell cycle arrest [92].
Steroids	Inhibition of tumor growth and stimulation of apoptosis in affected cells by beta-sitosterol. Elevation of antioxidant enzyme activity thereby annihilating oxidative stress damage caused by ROS [93].
Terpenoids	Elevation of cytotoxic activity in tumor cells thereby promoting apoptosis via the stimulation of specific enzymes and pathways [94].
Saponins	Stimulation of pro-inflammatory proteins and pro-survival genes, which in turn leads to activation of cell-cycle proteins, metalloproteinase and apoptotic proteins that regulate cell proliferation and metastasis [95].

Table 3. Major Phytoconstituents With Anti-Cancer Properties and Their Mechanism of Activity

Phytochemicals

Mechanism of anti-cancer activity

ROS: reactive oxygen species.

Flavonoids and phenolic compounds

The flavonoid structure’s numerous hydroxy groups, combined with a highly conjugated electron system, allow them to act as a free radical scavenger via hydrogen atom or electron-donating activities. They can also inhibit the formation of ROS and act as pro-oxidative compounds [82, 83]. phenolic compounds also exert their preventive role though cell cycle arrest, apoptosis, and most importantly, scavenging free radicals responsible for carcinogenesis and its progression [51, 84-86].

Alkaloids

Alkaloids are a group of ring structure nitrogen containing organic compounds with a wide range of anti-cancer activity [87]. These compounds take part in cancer inhibition via prevention of enzyme topoisomerase activity which is involved in DNA imitation, inducing apoptosis and expression of p53 gene [88-90]. Further, some groups (indole, pyrrole, isoquinoline, etc.) of alkaloids have been reported to exhibit cytotoxic activities against various cancer cell lines by inducing autophagy, necroptosis and apoptosis under the influence of various proteins involved in the apoptotic pathway [91].

Tannins

Inhibition of proliferation of cancerous cells by downregulating the expression of anti-inflammatory enzymes, anti-apoptotic proteins and regulation of specific pathways responsible for tumor cell migration as well as induction of cell cycle arrest [92].

Steroids

Inhibition of tumor growth and stimulation of apoptosis in affected cells by beta-sitosterol. Elevation of antioxidant enzyme activity thereby annihilating oxidative stress damage caused by ROS [93].

Terpenoids

Elevation of cytotoxic activity in tumor cells thereby promoting apoptosis via the stimulation of specific enzymes and pathways [94].

Saponins

Stimulation of pro-inflammatory proteins and pro-survival genes, which in turn leads to activation of cell-cycle proteins, metalloproteinase and apoptotic proteins that regulate cell proliferation and metastasis [95].