Beta-Caryophyllene Enhances the Anti-Tumor Activity of Cisplatin in Lung Cancer Cell Lines through Regulating Cell Cycle and Apoptosis Signaling Molecules

Abstract

Beta-Caryophyllene (BCP), a natural bicyclic sesquiterpenes, is an abundant biomolecule in red pepper and other plants. Recently, it was reported to reduce the growth and the proliferation as well as enhance the apoptosis in numerous cancer cells, including colorectal, ovarian, bladder cancer and lung cancer. On the other hand, the combination therapy of cisplatin (CDDP) with other phytochemical compounds has synergistically enhanced the killing effect of CDDP on several types of cancer. In the current model, we have tested the role of BCP in enhancing the anti-tumor activity of CDDP on lung cancer cell lines. The results showed that BCP is not toxic at moderate doses and it can prevent lung cancer progression in doses above 75 µM. However, when being combined with CDDP, BCP improved the former chemotherapeutic function through regulating cell cycle, apoptosis and EMT signaling molecules. Gene and protein expression analysis showed that the combined treatment of CDDP and BCP significantly upregulated the level of the cyclin-dependent kinase inhibitor, CDKN1A, and the inhibitor of the apoptosis, BCL-xl2. In addition, the combination treatment reduced the protein level of the apoptosis regulator, BCL-2. Moreover, BCP appears to prohibit the EMT process that is associated with CDDP chemotherapy since the combination treatment induced a significant increase in the level of the epithelial cell marker E-cad that was reduced in CDDP-treated cells. In agreement with that, the combined treatment managed to modulate the effect of CDDP on the mesenchymal transcription factor ZEB-2. Additionally, molecular docking has been conducted to check the virtual interaction of BCP with these and other signaling molecules, but only cyclin-dependent kinase CDK6 was found to virtually bind with BCP, and at four sites with higher and stable biding energy (−7.8). Together, these data indicate that BCP enhances CDDP chemotherapeutic function through regulating the cell cycle, the apoptosis and EMT signaling molecules.

Cisplatin‐resistance induces lung squamous carcinoma cell growth by nicotine‐mediated α7nAchR/HDAC1/Cyclin D1/pRb cell cycle activation

“…The CDDP causes HDAC1 to activate E2F cancer-suppressor genes, inhibiting their transcription. 23,[24][25] These results suggest that nicotine may be necessary for HDAC1 carcinogenic contentmediated advanced development or chemotherapy treatment failure in lung cancer. 26 The intricate relationship between nicotine, HDAC1, and cisplatin resistance carries significant therapeutic implications.…”

“…This study unveils the active role of nicotine in inducing cisplatin resistance in lung cancer, emphasizing the importance of understanding the molecular dynamics of HDAC1 activation. The CDDP causes HDAC1 to activate E2F cancer‐suppressor genes, inhibiting their transcription 23,24‐25 . These results suggest that nicotine may be necessary for HDAC1 carcinogenic content‐mediated advanced development or chemotherapy treatment failure in lung cancer 26 .…”

Effects of β-caryophyllene and oxygen availability on cholesterol and fatty acids in breast cancer cells

“…Over the last decade, numerous studies have shown that BCP exhibits anti-proliferative properties across various carcinoma cell lines [23,[60][61][62][63][64][65][66] but hypoxia was not addressed as a specific issue despite the hypoxic nature of most solid tumors [67]. In the present study, we hypothesized that BCP might reverse the hypoxic phenotype of TNBC cells.…”

β­caryophyllene oxide induces apoptosis and inhibits proliferation of A549 lung cancer cells

“…Based on these results, a hypothesis for the anticancer action of CPO has been proposed. In a new study, researchers were able to demonstrate that CPO inhibited the growth of lung cancer using the A549 cells [ 24 ].…”