A Theranostic and Precision Medicine Approach for Female-Specific Cancers

A Theranostic and Precision Medicine Approach for Female-Specific Cancers provides information regarding ongoing research and clinical data surrounding female specific cancers (breast, cervical, ovarian and endometrial cancers). The book encompasses detailed descriptions about diagnostics and therapeutic options for easy understanding, focusing on the subject matter with a broader range of treatment options. In addition, it explores new theranostics, i.e., diagnostic, therapeutic and precision medicine strategies currently being developed for FSCs. This book is a valuable resource for cancer researchers, clinicians, graduate students and other members of biomedical field who need to understand the most recent and promising approaches to manage FSCs.

• Explores new diagnostic biomarkers surrounding the early detection and prognosis of FSCs
• Examines new genetic and molecularly targeted approaches for the treatment of these aggressive diseases
• Discusses new theranostic approaches that combine diagnosis and treatment through the use of nanotechnology in FSCs
• Addresses how these various advances can be integrated into a precision and personalized medicine approach that can eventually enhance patient care

• Language: English
• Publisher: Academic Press
• Release date: Nov 6, 2020
• ISBN: 9780128226926

Book preview

(AACR).

Preface

Rama Rao Malla, Cancer Biology Lab, Department of Biochemistry and Bioinformatics, Institute of Science, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, India

Ganji Purnachandra Nagaraju, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States

In 2002, Funkhouser introduced the concept of theranostics, a strategy that combines diagnostic and therapeutic methods through the simultaneous probing, imaging, and targeted delivery of cytotoxic compounds to cancer tissues. This approach aims at improving cancer diagnosis and prognosis to inform personalized therapeutic regimens tailored to each patient’s specific needs. These new approaches could finally accomplish better treatment results for patients with female-specific cancers (FSCs), resulting in a precision medicine approach allowing early detection, management, and targeted tumor therapy. In this book, I compile this information thoroughly and accurately by exploring the new theranostic (i.e., diagnostic, therapeutic, and precision medicine) strategies currently being developed for FSCs.

FSCs include breast cancer, cervical cancer, ovarian cancer, and endometrial cancer. They are very lethal and are projected to become more malignant in the near future. This heavy burden is due to the lack of effective early detection methods and to the emergence of chemoradioresistance. Attempts at improving the outcome of FSCs by incorporating cytotoxic agents such as chemo drugs have been so far disappointing. These results indicate that the main challenge remains in the primary resistance of FSC cells to chemotherapy in the majority of patients. Therefore, improvement in the outcomes of FSCs is dependent on the introduction of new agents that can modulate the intrinsic and acquired mechanisms of resistance.

The increased understanding of the genetic, epigenetic, and molecular pathways dysregulated in FSCs has revealed the complexity of the mechanisms implicated in tumor development. These include alterations in the expression of key oncogenic or tumor-suppressive miRNAs, modifications in methylation patterns, the upregulation of key oncogenic kinases, and so on. This knowledge will allow the development of novel biomarkers that aid in the early diagnosis and management of these deadly diseases. It will also pave the way for the design of innovative therapeutic compounds targeted against specific signaling pathways upregulated during cancer progression.

In this book, we precisely focus on the subject matter with broader range of treatment options. Further, we compile this information thoroughly and accurately by exploring the new theranostic (i.e., diagnostic, therapeutic, and precision medicine) strategies currently being developed for FSCs. Further, this book provides an understanding of the roadblocks of chemotherapy in patients with newly diagnosed and metastatic FSCs. It also provides an in-depth understanding of the treatment options available currently as well as prospective options. Finally, it explores how these various advances can be integrated into a precision and personalized medicine approach that can eventually enhance patient care.

Chapter 1: Role of selected phytochemicals on gynecological cancers

Dariya Beguma; Neha Merchantb; Ganji Purnachandra Nagarajub    a Department of Biosciences and Biotechnology, Banasthali University, Banasthali, Rajasthan, India

b Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States

Abstract

Gynecological malignancies constitute cervical, uterine, and ovarian cancers with cervical cancer being rated as the second-most predominant malignancy in women globally. The therapeutic outcome always depends on the stage of cancer correlated with the disease level and its metastasis. The conventional therapeutic options include resection through surgery, chemotherapy, and radiotherapy. These treatment options cause tumor recurrence or adverse toxic effects. Furthermore, they develop dysregulated oncogenes and tumor suppressors. This inhibits apoptosis and enhances metastasis. This disillusioned clinical outcome is associated with poor prognosis. Thus, the conventional therapies require novel medications to prevent toxic effects and sensitize tumor cells toward the chemo-radiotherapies. Phytochemicals include bioactive compounds derived naturally from plants. These bioactive compounds are found to antagonize the dysregulated gene and enhance the efficacy of conventional therapies when used in combination. In this chapter we examine the role of selected phytochemicals, including resveratrol, genistein, and curcumin, that are now widely used for cancer therapy alone and in combination with conventional therapies. We also discuss the formulation of these bioactive compounds and novel nano-formulations to improve the bioavailability, stability, and pharmacokinetics of the drug used.

Keywords

Gynecological cancer; Prognosis; Uterine cancer; Ovarian cancer; Cervical cancer; Phytochemicals; Resveratrol; Genistein; Curcumin

Abbreviations

AgNPs 

silver nanoparticles

AHR 

aryl hydrocarbon receptor

ATR 

serine/threonine-protein kinase

COX-2 

cyclooxygenase-2

CXCR4 

(C-X-C) chemokine receptor type 4

DHA 

dihydroartemisinin

DHS 

dihydroxystilbene

EGCG 

epigallocatechin gallate

EGFR 

epidermal growth factor receptor

EMT 

epithelial-mesenchymal transition

ER α, β estrogen receptor alpha, beta

ER 

endoplasmic reticulum

ERK 

extracellular signal-regulated kinase

FOXO3 

Forkhead box transcription factors

GAL-3 

galectin-3

HER 

human epidermal growth factor receptor

HIF-1α 

hypoxia inducible factor-1 alpha

HNPG 

5-hydroxy-4′-nitro-7-propionyloxy-genistein

HPV 

human papillomavirus

IL 

interleukin

MK 

midkine

MMP 

matrix metalloproteinases

mTOR 

mammalian target of rapamycin

NF-κB 

nuclear factor kappa B

NQO1 

NAD(P)H:quinone oxidoreductase 1

OCSLCs 

ovarian cancer stem-like cells

P-gp 

permeability glycolprotein

PIK3 

phosphatidylinositol-4,5-bisphosphate 3-kinase

PTEN 

phosphatase and tensin homolog

STAT3 

signal transducer and activator of transcription 3

TGFA 

transforming growth factor alpha

TPGS 

tocopheryl polyethylene glycol

VEGF 

vascular endothelial growth factor

1: Introduction

Gynecological cancers are a group of malignant neoplasms of the female reproductive system that constitute the fourth most common cancers recorded in women [1]. The lack of awareness about these cancers, differentiating pathology, and shortage of screening opportunities are the chief causes for delayed diagnosis; these cancers are usually detected only at advanced stages. Among the gynecological cancers, endometrial, uterus, cervical, and ovarian cancers are the most commonly diagnosed that unfavorably affect the prognosis and clinical outcome of the patient [1]. The incidence and mortality rates of these types of cancers vary [2]. As per estimations from previous studies, 109,000 women were diagnosed with gynecological cancers in 2019; 33,100 deaths were recorded in the same year [3]. The common risk factors associated with genital system cancers are obesity, advanced age, use of fertility drugs, hormone replacement therapies, immunosuppression, and smoking. Infections including human papillomavirus (HPV) and chlamydia are also risk factors for cervical cancers [4]. Additionally, hereditary and family history of colorectal, breast, and ovarian cancers are also associated with the occurrence of disease [1]. Hysterectomy and tubal ligation may reduce the risk for uterine and ovarian cancers [5]. Thus, it is very crucial that women should be aware of the symptoms and signs that should be followed with regular screening and prevention strategies [1]. Moreover, therapy of cancer at its advanced stage and recurrence is always a challenge. Several attempts have been made by researchers to target the signaling pathways to control progression of cancer cells and to improve overall survival and prognosis of the patient.

The conventional therapies including chemo-radio-, immune-, and hormone therapy are included as therapeutic options prescribed based on the stage and type of malignancy. The chemo drugs that are frequently combined with conventional therapies are paclitaxel, doxorubicin, and cisplatin. However, these drugs are associated with toxic side effects and recurrent disease that develops from multidrug resistance. This resistance results from dysregulation of signaling pathways. Thus, there is a need to develop sensitive and personalized therapeutic strategies to reach higher therapeutic standards. Phytochemicals are naturally available molecules obtained from plants that constitute various bioactive properties. It was found that these compounds play a crucial role in antagonizing the dysregulated signaling pathways that cause malignancy. They can be easily obtained from healthy diets and can potentiate the conventional therapeutic strategies and enhance their efficacy when used together. Additionally, these phytochemicals incur no side effects and can target multiple signaling pathways responsible for cancer progression and proliferation [6]. Thus, these phytochemicals possess anticancer properties and can treat various cancers.

In this chapter we focus on gynecological cancers and the role of specific phytochemicals acting on signaling pathways to control tumor progression and induce apoptosis.

2: Uterine cancer

The uterus is a hollow organ located at the pelvic region that functions to support the development of a fetus. Anatomically, it has an inner layer, outer later, and bottom layer called the endometrium, myometrium, and cervix, respectively. Uterine cancer is the abnormal growth of cells in the uterine muscle. It occurs at two different parts of the uterus, based on which it is divided into two categories: commonly occurring endometrial cancer that forms the inner lining of the uterus and rarely occurring uterine sarcoma that forms the other tissue of the uterus. The uterine cancer is considered as one of the gynaecological tumors to have worst prognosis, and therapy includes resection of uterus. However, tumor recurrence requires effective therapeutic drugs. Pazopanib and trabectedin are most widely used for therapy, but are less effective as the tumor cells develop resistance resulted from the dysregulated signaling pathways. For instance, the mammalian target of rapamycin (mTOR) signaling pathway was found in elevated levels in women with gynecological cancer [7]. Similarly, endometrioid carcinoma results from the dysregulated DNA mismatch repair genes and mutations in phosphatase and tensin homolog (PTEN) and Kras [8–10]. Additionally, mutation in TP53, aberrantly acting HER2, and inactive expression of E-cadherin also results in endometrial cancer [11]. Moreover, uterus serous carcinoma results from mutated genes of p53, PIK3CA, HER2, and PPP2R1A, overexpression of cyclin D1/E, and downregulated expression of E-cadherin and p16 [12, 13]. Thus, the downregulated tumor suppressor genes and apoptotic genes, actively acting survival genes, and their signaling pathways develops chemoresistance. Therefore, detecting dysregulated genes and targeting them with active phytochemicals reflects a better therapeutic strategy for promoting chemosensitivity and better survival.

2.1: Resveratrol

The natural polyphenolic bioactive compound resveratrol, also known as 3,5,4′-trihydroxystilbene, can be found in grapes, peanuts, berries, and in high concentration in red wine [14]. It is widely popular for its antioxidant and anticancerous properties. As an anti-inflammatory, it regulates activation of certain proinflammatory proteins like nuclear factor kappa B (NF-κB) [15] and enzymes like cyclooxygenase-2 (COX-2) [16]. Resveratrol was determined to induce autophagy through activation of the AMPK-dependent signaling pathway. However, previously it was determined that autophagy also induces cancer progression [17]. Thus, Fukuda et al. [18] suggested that resveratrol along with chloroquine, an autophagy inhibitor, effectively induces apoptosis in Ishikawa endometrial cancer cells. This proved to be a therapeutic strategy for inducing apoptosis. However, the molecular mechanism behind resveratrol inducing autophagy and apoptosis remains a question. Adrenomedullin was found to exist in the cytoplasm of epithelial cells and stromal compartments [19]. Furthermore, adrenomedullin is upregulated at the time of endometrial repair and promotes angiogenesis by inducing endothelial cell proliferation and tube formation. Moreover, previously it was determined that the mRNA and peptide level of adrenomedullin is found in high levels under hypoxic conditions in various cancers by the activation of hypoxia inducible factor-1 alpha (HIF-1α) [20–23]. Evans et al. [24] further determined that this protein induces vascular endothelial growth factor (VEGF) secretion from primary cells of endometrial cancer. They also investigated for the first time that resveratrol and epigallocatechin gallate (EGCG) inhibit the secretion of adrenomedullin, thus reducing cancer incidence. The Wnt signaling pathway induces the accumulation of β-catenin that translocates to the nucleus. It later activates the transcription of c-myc and cyclin D, which promote tumorigenesis in various cancers [19]. Resveratrol was found to inhibit the Wnt signaling pathway in gastric and colorectal cancers. In uterine cancer cells, Sexton et al. [25] determined that resveratrol induces apoptosis when taken in high doses through COX-2 inhibition, which was tested in a group of uterine cancer cell lines, and regulates cancer cell proliferation. It was found to inhibit the expression of β-catenin and c-myc in a dose-dependent manner in uterine sarcoma cells. Thus, it inhibits cell proliferation and induces apoptosis via Wnt signaling pathway deactivation [26]. Later, Chen et al. [27] also determined that resveratrol inhibits β-catenin to control uterine fibroids. Uterine fibroids are the most common neoplasm of the uterus [28, 29] resulting from the aggressive production of the extracellular matrix (ECM) that includes collagens, fibronectin, and proteoglycans [30, 31]. Additionally, α-SMA, COL1A1, and β-catenin are found to be upregulated in ECM, developing into uterine fibroids. Resveratrol decreased their expression to mRNA and protein level in vitro and in vivo. However, the molecular mechanism involved is not yet explored and is yet to be determined [27]. Thus, resveratrol can be used as a complementary medicine for the therapy of cancer, however, further research is still essential for determining the efficacy of this compound.

2.2: Curcumin

Curcumin is an active phytocompound derived from the therapeutic Indian spice, Curcuma longa. It is used against various cancers like uterine leiomyosarcoma. It was previously demonstrated that curcumin inhibits tumor cell growth via downregulating the expression of tumor-promoting genes like mTOR [32, 33]. Wong et al. [34] determined that this bioactive compound downregulates phosphorylation of mTOR (Ser2448) together with its effectors p70S6 and S6 in uterine leiomyosarcoma cells. Later, they also proved the efficacy of intraperitoneal curcumin, which was administered in vivo in inhibiting the tumor growth in uterine leiomyosarcoma cells. They controlled the growth via inhibition of mTOR and inducing apoptosis. Low curcumin inhibits mTOR but showed no effect with Akt. Therefore, use of peritoneal curcumin enhanced the bioavailability and efficacy of curcumin in inhibiting Akt as well as mTOR. Androgen receptors are found to induce the activation of Wnt signaling pathways and are known to develop resistance. In another work, Feng et al. [35] revealed that curcumin in human endometrial carcinoma cells induce apoptosis via downregulating AR and β-catenin expression through the Wnt signaling pathway. Furthermore, curcumin also downregulates the expression of matrix metalloproteinase-2 (MMP-2) to its mRNA and protein level in a dose-dependent manner. Additionally, E-cadherin showed an inverse relationship with MMP-2 that is upregulated with exposure to high concentration of curcumin [36]. It was even evidenced from past studies that curcumin in endometrial cancer cells controlled the migration of tumor cells through the downregulation of MMP2 and MMP9-mediated extracellular signal-regulated kinase (ERK) pathway [37]. Slit-2, a secretory protein, identified as a molecule for axon guidance, is detected in various cancer cells. It plays a crucial role in inhibiting tumor cells and metastasis, inducing apoptosis, and cell cycle arrest. In support of this, Sirohi et al. [38] determined that curcumin induces the expression of Slit-2, to inhibit migration of tumor cells mediated via downregulation of CXCR4, MMP2, MMP9, and SDF-1. Thus, curcumin selectively affects aggregation and metastasis of endometrial tumor cells. However, the bioavailability and stability of curcumin is always a limitation. Researchers, therefore, have modified the structure of curcumin to produce analogues. For instance, the curcumin analogue, HO-3867, as suggested from earlier studies, mediates inhibition of signal transducer and activator of transcription 3 (STAT3) phosphorylation and induces apoptosis in various cancer cells [39, 40]. Tierney et al. [41] investigated that expression of pSTAT3 Ser727 is responsible for endometrial tumor growth and survival. They also suggested that HO-3867 was found to target pSTAT3 Ser727 to inhibit Ishikawa cell growth and proliferation via downregulation of active CDK5 and ERK1/2. Additionally, the upregulation of tumor suppressor protein p53, cleavage of caspase-3 and -7, and decrease in Bcl-2 and Bcl-xL was determined. It also induced cell cycle arrest at G2/M phases. This suggested that HO-3867 would potentially serve as a promising therapeutic strategy for cancer treatment. Furthermore, the development of nanotechnology enhanced the efficacy of phytochemical drugs. For instance, curcumin for the first time was successfully encapsulated in mixed micelles using PEG (15)-hydroxystearate and d-α-tocopheryl PEG (TPGS). The nano-designed micelles of curcumin were determined to have efficient anticancer property, enhanced intracellular uptake, and induced apoptosis. This resulted from downregulation of surviving expression in endometrial cancer cell lines. Additionally, it also regulated permeability glycolprotein (P-gp) efflux, preventing tumor cells from developing resistance and downregulating the expression of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-10 [42]. Similarly, the liposome encapsulated with curcumin was evidenced from the work of Xu et al. [43]. They determined that the liposome encapsulated with curcumin effectively suppressed the activation of NF-κB in vitro and in vivo against endometrial cancer cells. Additionally, it was also found to downregulate the expression of MMP-9. This indicates the therapeutic potentiality of curcumin against uterine cancer and its efficacy when encapsulated in nanoparticles. The clinical trials recorded for curcumin are illustrated in Table 1. However, further exploration of the phytochemical's molecular mechanism and evaluation of its safety and efficacy is essential.

Table 1

Source: www.clinicaltrials.gov.

2.3: Genistein

Genistein is a naturally available isoflavone extracted from soya-based products. It is widely known for its estrogenic effects and is encouraged for hormonal therapies as an alternative option [44, 45]. Moreover, it was elucidated from previous studies that genistein has antioxidant and antimetastatic properties. It was found to regulate the expression of various genes responsible for cell growth, angiogenesis, and apoptosis in vitro and in vivo. The antiproliferative efficacy of genistein was tested for clinical trials against various cancers including colorectal, prostate, and bladder cancers. It was also found to modulate the proliferation of uterine sarcoma. For instance, Hu et al. [46] determined that using Chinese herbal products including genistein, coumestrol, and daidzein along with tamoxifen controlled the risk of occurrence of endometrial cancer in Taiwanese female patients. Tamoxifen is administered for estrogen receptor–positive breast cancer in order to reduce recurrence; however, its continuous usage develops the risk for endometrial cancer. Therefore, consuming phytoestrogen Chinese herbal products along with tamoxifen reduces the risk for endometrial cancer. Similarly, genistein was also compared to estrogen given immediately or in later stages to ovariectomy rats for the risk of developing endometrial cancer. It was determined that the rat that was given estrogen in the later stage of ovariectomy developed an enhanced estrogen signaling cascade. This resulted in vigorous cell proliferation due to the activation of Ki67 and VEGF-A, which increased the risk of endometrial cancer. However, no such proliferation was detected in the rat that was given genistein, regardless of the time it was given. Thus, genistein renders low risk for the occurrence of endometrial cancer as compared to estrogen [47]. Moreover, the estrogenicity of genistein was also found to be similar to that of estradiol when compared in the expression profile of Ishikawa cells exposed to both genistein and estradiol prepared by Naciff et al. [48]. They determined that genistein also upregulates and downregulates the expression of multiple genes in a time- and dose-dependent manner involved in biological functions. These include FOS, EGFR1, FGFR2, SOX4, PTEN, and TGFA, which play a crucial role in the human endometrium. It is also found to induce DNA fragmentation and enhance apoptosis via upregulating the expression of pro-apoptotic proteins including BAX and BAD and activation of caspase-3 [49]. Furthermore, it increased the activation of p27, p53, and p21 and reduced the expression of β-catenin to control the growth of endometrial cancer cell progression [49]. Moreover, it induced apoptosis in endometrial cancer cells that developed resistance against doxorubicin. It was previously determined that taking genistein in high doses suppresses tyrosine kinase and DNA topoisomerases with the release of TGF-β and induces apoptosis [50]. Later, Di et al. [51] investigated the biological mechanisms involved with the activity of genistein to inhibit uterine leiomyoma via the TGF-β signaling pathway and the downstream genes actin A and Smad3. Their results suggest that downregulation of actin A and Smad3 control growth of uterine leiomyoma effectively when exposed to high doses of genistein. Even though genistein is widely known for its antiproliferative activity against tumors, its usage is limited due to its poor absorption in the gastrointestinal tract. Therefore, the structural alteration would potentiate the effect of the phytochemical. Bai et al. [52] determined the effect of 5-hydroxy-4′-nitro-7-propionyloxy-genistein (HNPG), an analogue of genistein. It was found to induce cell cycle arrest at G1 phase in Ji endometrial cell in vitro. Furthermore, it also downregulates the expression of cyclin D1, MMP-2, MMP-7, MMP-9, C-Myc, and β-catenin, inactivating the Wnt/β-catenin signaling pathway. Subsequently, this enhanced the stability and half-life of the drug. The clinical trials performed to determine the efficacy of genistein are illustrated in Table 1. Future investigations are essential to enhance the efficacy and stability of genistein to improvise the therapeutic strategies for the benefit of cancer patients.

3: Cervical cancer

Cervical cancer occurs in the cervical cells present toward the bottom part of the uterus that connects with the vagina. As estimated by the World Health Organization (WHO), cervical cancer is the fourth most recurrent cancer in females [53]. Cervical cancer in its preinvasive stage shows no symptoms, but the abnormal cells behave aberrantly and invade the adjacent tissues. The symptoms of cervical cancer include abnormal vaginal bleeding in between menstrual cycles and heavier bleeding than usual. Risk factors include persistent HPV infection, which subsequently leads to cancer. Additionally, smoking and using contraceptive pills are also associated with the risk of cancer occurrence [54]. Squamous cell carcinoma and adenocarcinoma are the two main types of cancers of the cervix, which is the determining factor for deciding the therapy and prognosis of the patient [55]. Surgery is always a primary choice for treatment, but tumor relapse and metastasis results in poor prognosis of the patient [56]. Chemotherapy would be the option to avert recurrence in the postoperative stage. The chemodrugs commonly prescribed include bevacizumab, pembrolizumab, and gemcitabine, with cisplatin as a combinational drug. However, development of resistance and adverse side effects always affects the quality of therapy. Therefore, there is a serious need for the exploration of therapeutic strategies that are less toxic to healthy cells and more consistent.

3.1: Resveratrol

Resveratrol is a phytoalexin, which is a naturally available bioactive compound obtained from berries, peanuts, and grapes [57]. It was demonstrated that phytoalexin exhibits multiple biological properties including antiproliferative, antimetastatic, antioxidative, and cardioprotective [58, 59]. Investigations from earlier research studies determined that phytoalexin has anticarcinogenic and apoptotic properties against various cancers. In cervical cancer, resveratrol induces radio-sensitization and apoptotic effect that are inhibitory to various signaling pathways associated with tumorigenesis [60]. For instance, STAT3, Notch, and Wnt signaling pathways play a crucial role in promoting cervical cancer and are found to be regulated by the activity of resveratrol. It was suggested to induce apoptosis and inhibit progression in HeLa and SiHa cell lines. This was further accompanied by the suppression of STAT3/JAK3, Notch, and Wnt signaling pathways [61]. The activity of STAT3 in cervical cancer was analyzed and it was determined that the three proteins, including suppressor of cytokine signaling 3 (SOCS3), SHP2, and protein inhibitor of activated STAT protein 3 (PIAS3), negatively regulate the STAT3 signaling pathway. These proteins are found to be downregulated in cervical cancer. It was determined that resveratrol inhibits the STAT3 signaling pathway to control progression in cervical cancer, elucidating changes in these three proteins [62]. Moreover, it was investigated that the expression of PIAS3 and SOCS3 are reduced in cervical cancer cells [62]. When treated with resveratrol, PIAS3 was upregulated threefold greater than SOCS3, which showed moderate enhancement. This eventually resulted in inhibiting JAK 1/2 enzyme activity and significantly suppressed the STAT3 signaling pathway in vivo [62]. Thus, triggering PIAS3 could serve as a therapeutic prognostic factor for determining the efficacy of resveratrol. Furthermore, Li et al. [63] determined that resveratrol activates the mitochondrial apoptotic signaling pathway. It upregulates caspase-3 and caspase-9 expression and downregulates antiapoptotic proteins including Bcl-2. It was found to induce cell cycle arrest at G2 phase via downregulating cyclin D1. The same group suggested that resveratrol potentiates the upregulation of tumor suppressor p53 in HeLa cells. Moreover, HPV infections are responsible for approximately 55% of cervical cancers. This results from the activation of E6 and E7 genes that inactivate various tumor suppressor proteins like p53. These genes are deactivated via ubiquitination and degraded by E3 ubiquitin ligase (E6-associated protein) [64]. Moreover, E3 ubiquitin ligase proteins like Mdm2 are activated when the environmental contaminants like halogenated hydrocarbons bind to the aryl hydrocarbon receptor (AHR) [65]. Thus, researchers suspect that this AHR activation may cause p53 ubiquitination and promote cervical cancer, however, its connection to cervical cancer proliferation is unclear. Flores et al. [66] determined that resveratrol along with α-naphthoflavone induced apoptosis and inhibited proliferation. Together they increased the half-life of p53 through the activation of E2F4/5 and induced G1/S phase cell cycle arrest. E2F4/5 activation induces suppression of tumors as well as induces cell cycle arrest at G1/S phase. Later, they suggested that AHR functions as per the cell type and cell transformation state. They showed that knocking of the AHR gene did not show any kind of decrease in cell proliferation or promote apoptosis. Thus, both α-naphthoflavone and resveratrol inhibit cell proliferation and induce apoptosis in HeLA, showing no effect on AHR. Similarly, Mukherjee et al. [67] used a combinational phytochemical drug TriCurin, which includes curcumin, EGCG, and resveratrol, against HPV E6 and E7 expression. They determined that TriCurin administered as a subcutaneous injection exhibited no side effects as detected in mice. It was found to downregulate the expression of HPV18 E6 and NF-κB with the upregulation of p53 and activation of caspase-3. Moreover, the combo drug used provided high stability and decreased cervical cancer tumor growth (80%–90%). Thus, this novel combo phytochemical drug can be administered as a promising therapeutic drug against HPV-related cancers. Previously, it was determined that HPV infection causes the dysregulation of p53, inducing apoptosis. Additionally, TRAIL, another protein, promotes apoptosis, but in a p53 independent way [68–70]. Thus, TRAIL can be encouraged as a therapeutic strategy to control cervical cancer apoptosis. Nakamura et al. [71] further determined that resveratrol inhibits the expression of survivin via phosphorylating its transcription factor STAT3. Inhibiting STAT3 enhances TRAIL expression and induces apoptosis. They even performed knockdown of survivin with siRNA that induced cell cycle arrest at G2/M phase and upregulated the expression of E-cadherin in the cervical cancer cell lines. Moreover, this treatment led to enhancement of cisplatin-induced apoptosis. Thus, this would be an ideal strategy to enhance the sensitivity of drug and induce apoptosis. Similarly, pterostilbene, otherwise called 3′,5′ dimethoxy-resveratrol, also exerts anticancer effects like resveratrol. It was found to induce apoptosis via disrupting the mitochondrial membrane and inhibiting the mTOR/PI3K/Akt pathway [72]. Phytoalexin is an effective anticancer drug, however, its bioavailability is always a limitation and it is not encouraged for further clinical trials. Recently, a few analogues were synthesized to enhance the bioavailability, stability, and efficacy against cancer progression. For instance, N-(4-methoxyphenyl)-3-5-dimethoxybenzamide [73] and (E)-8-acetoxy-2-[2-(3,4-diacetoxyphenyl)ethenyl]-quinazoline [74] are found to induce cell cycle arrest at G2/M phase via upregulating Chk1/2-cdc25 and p53-p21 tumor suppressor protein in ATM/ATR dependent way. Additionally, researchers have also synthesized nanoparticles encapsulated with resveratrol to improve the efficacy of the drug. More recently, the green synthesized gold nanoparticle that is capped with resveratrol was combined together with doxorubicin to enhance its efficacy in inhibiting cervical carcinoma [75]. This novel drug nano-vehicle efficiently improved the efficacy of the drug without causing cytotoxicity to the healthy cells. Thus, developing nanocomplexes is essential as an advanced application for cancer diagnosis and