2.1. Phytochemicals used as adjuvant for chemotherapy
Despite its effectiveness, conventional chemotherapy has may side effects. Approaches focusing on the combinational efficacy of promising dietary phytochemicals can be efficacious in cancer chemoprevention. Various phytochemicals which have increased the efficacy of chemotherapeutic drugs are discussed below and shown in Table. 2.
Apigenin is a natural plant flavone commonly found in fruits and vegetables like grapefruit, orange, onion, zlicorice root etc (Shuklaet al. , 2010). Apigenin treatment increased the susceptibility of HNC cells to chemotherapy as it enhanced the cytotoxicity of Cisplatin and 5-Fu to SCC25 cells (Chan et al. , 2012). Betulinic acid also showed additive effects along with cisplatin to inhibit the growth of HNC. Good bioavailability & the good safety profile of Caffeic Acid Phenethyl Ester [CAPE, a component of honey beehive] makes it safe to use through oral route and an ideal candidate for adjuvant therapy. CAPE can be applied daily for long duration as a topical cream or mouth wash for regression of oral cancer. CAPE along with 5-fluorouracil shows additive inhibitory effect on proliferation of TW 2.6 an OSCC cancer cell line and decreases undesired side effects and other uncomfortable symptoms in patients due to 5-fluorouracil. CAPE treatment inhibits both total abundance & phosphorylation of NF-κB at Serine 536 in TW 2.6 cells (Kuo et al. , 2013). Another flavonoid Genistein also showed synergistic effects with cetuximab via inhibition of EGFR signaling pathway both in in-vitro in oral cancer cells HSC-3 and KB as well as in in-vivo (Park et al. , 2010).
EGCG also enhanced the cisplatin-mediated chemosenstivity by decreasing the ABCG2 and ABCG2 transporter genes (reputed molecules of treatment resistance of CSCs). Combination of EGCG along with cisplatin significantly inhibited the tumor formation and induced apoptosis in xenograft nude mice model (Lee et al. , 2013).
Guggulsterone an important phytosterol isolated from the gum resin of the Commiphora mukul plant and shows anti-inflammatory activity by inhibiting inducible nitric oxide synthetase (iNOS) (Meselhy, 2003; Singh et al. , 2003). Gugglesterone was found to enhance the efficacy of cisplatin, erlotinib and cetuximab in HNC cell lines as well as in in-vivo xenograft mice model (Leeman-Neill et al. , 2009).
Honokiol (HNK) is another active compound present in leaf and bark ofMagnolia officinalis which has shown chemopreventive and chemotherapeutic effects in many tumor models like breast, melanoma, prostrate and skin (Hahm et al. , 2008). HNK minimized the chemoresistance by downregulating the P-glycoprotein expression in MDR SCCHN cells. It arrested cell cycle and induced apoptosis via locking of survival signals including PI3K/Akt & Mcl-1 and showed synergistic effect with taxol (Wang et al. , 2007). It also enhanced the efficacy of Paclitaxel in multi drug resistant [MDR] HNC cells [KB-8-5, KB-V1 & KB-C1]. HNK induced mitochondrial & death receptor dependent apoptosis in MDR KB cells via inhibiting the EGFR-STAT3 pathway (Wang et al. , 2014). In another study HNK decreased the self-renewal & survival of OCSCs dose dependently via downregulation of ALDH1 & CD44.Thus HNK potentiates the effect of cisplatin via reducing the stemness characteristics (Chang et al. , 2018). HNK is aphytochemicals which can be used with different chemotherapeutics drugs like paclitaxel, Taxol, Cisplatin to sensitize chemoresistant HNC and may give a better therapeutic opportunity for HNC cure.
Benzylisothiocyanate (BITC) is an Isothiocyanate (ITC) of specific attraction for anticancer therapy, due to its capability to inhibit cell growth & induce apoptosis in many types of cancers including HNC (Wuet al. , 2009). BITC sensitized the HN8, HN12 and HN30 cells to cisplatin treatment. Combined treatment reduced cell viability significantly than either treatment alone. It also inhibited expression and regulated the localization of EMT marker vimentin (Wolf et al. , 2014).
Lupeol is a pentacyclic triterpene, commonly found in olive, green pepper, mango, white cabbage, strawberry, and grapes and posses many pharmacological activities including anti-oxidant, anti-inflammatory, anti-angiogenic and anticancer properties (Liu et al. , 2021). Lupeol was found to re-sensitize primary HNC tumor sample, already treated with cisplatin. Synergistic chemosensitization effect with cisplatin was observed with high NF-ĸB activity in-vitro . 2mg/animal dose of lupeol significantly decreased the tumor volume and also suppressed local invasion and nodal metastasis in an Orthotopic Nude Mouse Model (Lee et al. , 2007). Luteolin also showed synergistic effect with paclitaxel in HNC by enhancing inhibition of tumor growth (Yang et al. , 2008).
Quercetin and cisplatin when given simultaneously showed synergistic effects and allowed the use of less toxic doses of chemotherapy for management and treatment of HNC (Sharma et al. , 2005). A xenographic study also showed positive effect when combination of quercetin and cisplatin was given and an improved prognosis was observed in OSCC patients (Chen et al. , 2012b).
Resveratrol a phytochemical present in red wine showed synergistic effect with various cancer therapeutic regimes in head and neck cancer. Quan et al (2009) reported that resveratrol shows synergistic effect with paclitaxel as a result of downregulation of the expression of hypoxia inducible factor 1alpha [HIF-1α], multidrug resistance gene 1 (mdr1), multidrug resistance-associated protein 1 (MRP1) and increased the apoptotic rate in CNE2 nasopharyngeal carcinoma cell line (Quanet al. , 2009). Resveratrol also showed synergistic effect with Taxol and inhibited the growth of human laryngeal carcinoma cell line Hep-2. Apoptosis was induced via increase level of Bax, PARP, TRIB3, caspase-3,8 and downregulating Bcl-2 and XIAP (Lu et al. , 2016).
Salvianolic acid B [Sal-B] is a promising anticancer agent in HNC. Zhao et al (2010) studied the combination effect of Salvianolic acid B with low doses of celecoxib in 4 HNC cell lines [JHU-013, JHU-06, JHU-022, & JHU-011]. The anticancer efficacy was greatly increased in JHU-013 and JHU-022 cell line when combination was given. 40mg/kg/day of Sal-B & 2.5mg/kg/day of celecoxib significantly reduced the JHU-013 xenograft tumor growth as compared to mice treated with full dose of celecoxib or Sal-B alone.
Silibilin (SB) a phytochemical from milk thistle plant also shows synergistic activity with various chemotherapeutic drugs like 5-fluorouracil, doxorubicin, etc to prevent the renewal and growth in HNC-TICs. Silibilin suppress the proliferation of both OECM1 and SAS cells and downregulates the CD133 positivity, ALDH1 activity, self-renewal property, stemness signatures expression and chemoresistance in dose-responsive manner. It also decreased the mRNA and protein expression of Nanog, Oct-4 and nestin in both these HNC-TICs (Chang et al. , 2015).
The combination of TQ, with Cisdiamminedichloridoplatinum (II) (CDDP) induced greater cytotoxicity in UMSCC-14 cell lines as compared to normal oral epithelial cells OEC. Both TQ and CDDP show synergistic effect on UMSCC-14 and OEC via change in expression levels of Bcl-2, p53 and caspase-9 protein resulting in increased apoptosis (Alaufi et al. , 2017).