Biochemical and molecular studies on the potentiating effect of and#946; caryophyllene on paclitaxel in cancer cell lines insight into combination therapy

Abstract

Cancer is characterized by the uncontrolled division of cells in the body hampering the normal physiology and functioning of cells and tissues and leads to death if left untreated. Cancer is classified into different types based on the tissue origin. The global burden and incidences have been increasing steadily with the maximum of deaths reported worldwide. Major reasons are population growth, aging, lifestyle changes, various intrinsic factors including oncogenes, genetic factors, microenvironment and several extrinsic factors. Breast cancer is the most frequent form of cancer diagnosed in over 154 countries. Invasive and non-invasive cancers are the two different types of major breast cancers, with a high chance of lifetime risk of developing cancers. Old age plays a major role with incidence seen at an average of 50 years of age. Breast cancer has a striking genetic correlation with breast cancer gene (BRCA1 and BRCA2 genes). Obesity, diet, nutrition physical inactivity, low parity rate are responsible for the aetiology of breast cancer. Many signalling pathways have been dysregulated in cancer important of which are survival pathways including nuclear factor kappa light chain enhancer of activated B cells (NFkB), Akt kinases along with apoptosis pathway. These signalling pathways have been an attractive target for various cancer therapies, many drugs were used as inhibitors or inducers of these signalling pathways. The bioenergetics profile are modulated in cancer cells, therefore modified glycolysis and resulting ATP and NADH levels are drastically altered which gives a survival advantage to cancer. Man therapeutics targeting glycolysis and bioenergetics have shown promising effect. Ovarian cancer is another common form of cancers among women and are heterogeneous. Breast cancer incidence in a family is one of the strongest risk factors and are mostly found at a median age of 63. BRCA1 and BRCA2 gene mutations have been linked to ovarian cancer with other factors. Paclitaxel (PTX) is a standard chemotherapy agents for both breast and ovarian cancers. Paclitaxel was first isolated from Western Yew tree and now are prepared by chemical synthesis methods. Several combinational therapy with paclitaxel has been tried in the recent years and new combinational therapies are in demand. One of the major reasons for combination therapy is to achieve better efficiency, elude resistance and relapse. Other reasons include chemotherapy induced side effects important of which is chemotherapy induced peripheral neuropathy, neurotoxicity and pain. These limitations could be overcome by using agents that could help reduce the dose and alleviate newline