# Electronic Cigarettes' Toxicity: From Periodontal Disease to Oral Cancer
## 5 Nicotine's Influence on Chemotherapy Drug Resistance  
Oral cancers treatment is usually represented by surgery, radiotherapy, chemotherapy, targeted agents, and immunotherapy. Chemotherapy of oral cancers includes several therapeutic agents (Table 3) [82]. Doctors observed that smoking cancer patients have lower chemotherapy response rates, mainly due to nicotine's ability to inhibit apoptosis and induce chemoresistance in cancer cells. Nicotine inhibited the apoptotic effect of cisplatin, vinblastine, paclitaxel, and doxorubicin [60; 90]. [PERSON] et al. assess the impact of nicotine on cisplatin-induced apoptosis in human oral cancer cells and observed that nicotine exposure inhibited apoptosis induced by cisplatin. They demonstrated that survivin and the Akt pathway play an important role in this process [91]. [PERSON] et al. investigated the effects of nicotine on oral and lung cancer cells and demonstrated that activated cell membrane-localized nAchRs form complexes with EGFR and VEGFR, while activated mitochondrial-nAchRs form complexes with phosphatidylinositol 3-kinases (PI3K) and Src (proto-oncogene tyrosine-protein kinase). The results of these interactions are increased cell proliferation, upregulated expression of cyclin D1 (a protein required for progression through the G1 phase of the cell cycle,) activation of \begin{table}
\begin{tabular}{c c c} \hline \hline
**Active Compound** & **Mechanism of Action** & **Reference** \\ \hline Cisplatin & Induces apoptosis in cancer cells by crosslinking with the purine bases on the DNA, causing DNA damage & [83; 84] \\ \hline Carboplatin & Similar mechanism with cisplatin, but with lower reactivity and slower DNA binding kinetics & [83] \\ \hline Paclitaxel & Binds to \(\beta\)-subunit of the tubulin protein of the microtubules, promotes the assembly of tubulin into microtubules and prevents the dissociation of microtubules, blocking cell cycle progression, preventing mitosis, and inhibiting cancer cells growth & [85] \\ \hline Docetaxel & Similar mechanism to paclitaxel-binds to \(\beta\)-tubulin, and it inhibits the proper assembly of microtubules into the mitotic spindle, arresting the cell cycling during G2/M & [86] \\ \hline \multirow{3}{*}{5-fluorouracil} & Pyrimidine antagonist-antimetabolite with a similar structure to naturally occurring compounds that are required for the viability and division of a cell; it inhibits the replication or the repair of DNA & [87; 88] \\ \hline Hydroxyurea & Inhibits ribonucleotide reductase and blocks the formation of nucleotides needed for DNA synthesis and repair & [87] \\ \hline \multirow{3}{*}{Methotrexate} & Folate antagonist; it inhibits dihydrofolate reductase, affecting the de novo synthesis of purines used in DNA replication & [87; 89] \\ \cline{1-1} \cline{2-3}  & Capsitabine & Similar mechanism with 5-fluorouracil & [87] \\ \hline \hline \end{tabular}
\end{table} 
Table 3: Chemotherapy agents used in oral cancer treatment. ERK1/2 (extracellular signal-regulated kinases that act in a signaling cascade regulating proliferation, differentiation, and cell cycle progression), but also the inhibition of the apoptogen-induced opening of mPTP (the mitochondrial permeability transition pore). The inhibition of apoptogen-induced opening of mPTP can represent a mechanism that explains nicotine's protection of cancer cells from chemotherapy-induced apoptosis. mPTP opening can cause apoptosis due to the massive swelling of mitochondria, which leads to membrane rupture and release of components [57]. In another study, [PERSON] et al. investigated the activation of survival pathways in colon cancer cells exposed to nicotine. The results revealed the involvement of \(\alpha\)7-AChRs in cell growth and apoptosis. Additionally, nicotine increased the expressions of PI3K, P-Akt/Akt, PKC, ERK1/2, survivin, and P-Bcl2 [92].