A number of monoterpenes have been reported to exert chemopreventive effects against tumors . Of these, the anti-tumorigenic activity of d-limonene is well-established. Numerous studies have demonstrated the protective effects of d-limonene against chemical-induced tumors in various tissue types such as breast, intestine, pancreas, liver, and colon . Lu et al. revealed that d-limonene could inhibit the proliferation of human gastric cancer cells by inducing apoptosis. Later, it was demonstrated that apoptosis of tumor cells by d-limonene could be mediated by the mitochondrial death pathway via activated caspases and PARP cleavage as well as by the suppression of the PI3K/Akt pathway. In addition, positive effects on NK (Natural Killer) activities were demonstrated not only in the in vitro treatment of tumor cell lines with monoterpenes released from trees, such as d-limonene and α-pinene, but also in forest bathing trips by increasing intracellular levels of anti-tumor proteins such as perforin, granulysin, and granzymes A/B.

https://pubmed.ncbi.nlm.nih.gov/25401162/
https://pubmed.ncbi.nlm.nih.gov/8886130/
https://pubmed.ncbi.nlm.nih.gov/15237454/
https://pubmed.ncbi.nlm.nih.gov/23117412/
https://pubmed.ncbi.nlm.nih.gov/19568839/

Anti-tumor effects of pinenes are well established on tumor lymphocytes as well as tumor cell lines . Matsuo et al. identified proapoptotic and anti-metastatic activities of α-pinene in a melanoma model. Later, it was revealed in human hepatoma Bel-7402 cells that the proapoptotic effect of α-pinene is associated with induction of G2/M cell cycle arrest . In addition, α-pinene triggers oxidative stress signaling pathways in A549 and HepG2 cells . However, Kusuhara et al. reported that mice kept in a setting enriched with α-pinene showed reduction in melanoma sizes, while in vitro treatment of melanoma cells with α-pinene had no inhibitory effect on cell proliferation, suggesting that the in vivo result may not be due to a direct effect of α-pinene. Investigation of β-pinene also revealed its cytotoxic activity against cancer and normal cell lines with a more pronounced effect on neoplastic cells in the majority of cases, showing acceptable chemotherapeutic potency.

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https://pubmed.ncbi.nlm.nih.gov/21756878/
https://pubmed.ncbi.nlm.nih.gov/25837931/
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https://pubmed.ncbi.nlm.nih.gov/22361888/
https://pubmed.ncbi.nlm.nih.gov/24708588/
https://pubmed.ncbi.nlm.nih.gov/18814213/

Perillyl alcohol is a naturally occurring monoterpene, and a metabolite of limonene. Despite preclinical evidence of anticancer activity, perillyl alcohol appeared to have no clinical antitumor activity upon oral administration to patients with advanced colorectal carcinoma . However, currently, it is under preclinical development as a potential clinical treatment for patients with brain tumor . Perillic acid is a major metabolite of perillyl alcohol. Upon examining the effects of perillic acid on lung metastasis induced by melanoma cells in mice, it was observed that administration of perillic acid remarkably reduced the metastatic tumor nodule formation by exerting an inhibitory effect on cell growth by G1 arrest.

https://pubmed.ncbi.nlm.nih.gov/12794248/
https://pubmed.ncbi.nlm.nih.gov/26282951/
https://pubmed.ncbi.nlm.nih.gov/12175534/
https://pubmed.ncbi.nlm.nih.gov/17888568/

p-Cymene has been reported to have cytotoxic effects on tumor cell lines . Recently, Li et al. evaluated beneficial effects of p-cymene on in vitro TPA-augmented invasiveness of HT-1080 cells, and found that it inhibits MMP-9 expression, but enhances TIMP-1 production along with the suppression of ERK1/2 and p38 MAPK signal pathways in tumor cells, suggesting that p-cymene is an effective candidate for the prevention of tumor invasion and metastasis.

https://pubmed.ncbi.nlm.nih.gov/23453306/
https://pubmed.ncbi.nlm.nih.gov/27476935/

Myrcene, the acyclic monoterpene, also exhibits significant antiproliferative and cytotoxic effects in various tumor cell lines such as MCF-7 (breast carcinoma), HeLa (human cervical carcinoma), A549 (human lung carcinoma), HT-29 (human colon adenocarcinoma), P388 (leukemia), and Vero (monkey kidney) as well as mouse macrophages. Essential oil from Vepris macrophylla demonstrated a strong cytotoxic effect, suggesting that the effect may be attributed to the presence of specific components, among which is myrcene.

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https://pubmed.ncbi.nlm.nih.gov/23495153/

Terpenes with more complex structures than monoterpenes, including sesquiterpenoids derived from sesquiterpenes by biochemical modifications, have demonstrated anticancer ability as well. The anticancer effect of various sesquiterpenoids is mediated via inhibition of inflammatory responses, prevention of metastasis, and induction of apoptosis . α-Caryophyllene, known as humulene, is a naturally occurring monocyclic sesquiterpene. BCP, an isomer of α-caryophyllene, has been identified as an active component of an essential oil mixture that not only prevents solid tumor growth and proliferation of cancer cell lines but also inhibits lymph node metastasis of melanoma cells in high-fat diet-induced obese mice. Sarvmeili et al. reported that Pinus eldarica essential oil, of which BCP was the major component, exerts cytotoxic effects on HeLa and MCF-7 cell lines.

https://pubmed.ncbi.nlm.nih.gov/12672998/
https://pubmed.ncbi.nlm.nih.gov/26025912/
https://pubmed.ncbi.nlm.nih.gov/26132906/
https://pubmed.ncbi.nlm.nih.gov/28003841/

As described above, numerous in vitro and in vivo experimental results have demonstrated that the toxicity of terpene affects mainly cancer cells without harming healthy ones, confirming their efficiency in chemotherapeutic treatment of cancer. Thus, it is noteworthy that the use of terpene and its derivatives can be considered to potentiate the action of existing conventional therapies

https://pubmed.ncbi.nlm.nih.gov/18053325/
https://pubmed.ncbi.nlm.nih.gov/24831562/